APITOXINA & DOLOR
| 1: Brain Res. 2006 Jan 31; [Epub ahead of print] |
Antinociceptive
effect and the mechanism of bee venom acupuncture (Apipuncture) on inflammatory
pain in the rat model of collagen-induced arthritis: Mediation by alpha(2)-Adrenoceptors.
Baek
YH, Huh
JE, Lee
JD, Choi
DY, Park
DS.
Department of Acupuncture and Moxibustion, College of Oriental Medicine, Kyung
Hee University, #1 Hoegidong, Dongdaemungu, Seoul 130-702, South Korea.
The antinociceptive effect and the mechanism of bee venom acupuncture (BVA)
on inflammatory pain, especially in the rat model of collagen-induced arthritis
(CIA), have not yet been fully studied. This study was designed to investigate
the antinociceptive effect and its mu-opioid and alpha(2)-adrenergic mechanism
of BVA in the CIA rat model. To induce CIA, male Sprague-Dawley rats were
immunized with bovine type II collagen emulsified in Freund's incomplete adjuvant
followed by a booster injection 14 days later. The antinociceptive effect
was evaluated by tail flick latency (TFL). After induction of arthritis, the
inflammatory pain threshold decreased as time passed, and there was no big
change of the pain threshold after 3 weeks. Three weeks after the first immunization,
BVA (0.25 mg/kg) injected into the Zusanli acupoint (ST(36)) showed the antinociceptive
effect. Furthermore, the antinociceptive effect of BVA was blocked by yohimbine
(alpha(2)-adrenergic receptor antagonist, 2 mg/kg, i.p) pretreatment, but
not by naloxone (mu-opioid receptor antagonist, 2 mg/kg, i.p.) pretreatment.
These results suggest that BVA can relieve inflammatory pain in CIA and the
antinociceptive effect of BVA can be mediated by alpha(2)-adrenergic receptor.
PMID: 16457792 [PubMed - as supplied by publisher]
| 2: Neuroscience. 2006;138(2):631-640. Epub 2006 Jan 30. |
Effects of
bee venom peptidergic components on rat pain-related behaviors and inflammation.
Chen YN, Li KC, Li Z, Shang GW, Liu DN, Lu ZM, Zhang JW, Ji YH, Gao GD, Chen J.
Institute for Functional Brain
Disorders and Institute for Biomedical Sciences of Pain, Tangdu Hospital,
Fourth Military Medical University, #1 Xinsi Road, Baqiao, Xi'an 710038, PR
China.
To identify the active components of honeybee venom in production of inflammation
and pain-related behaviors, five major peptidergic subfractions were separated,
purified and identified from the whole honeybee venom. Among them, four active
peptidergic components were characterized as apamin, mast-cell degranulating
peptide (MCDP), phospholipase A(2) (PLA(2))-related peptide and melittin,
respectively. All five subfractions were effective in production of local
inflammatory responses (paw edema) in rats although the efficacies were different.
Among the five identified subfractions, only MCDP, PLA(2)-related peptide
and melittin were able to produce ongoing pain-related behaviors shown as
paw flinches, while only apamin and melittin were potent to produce both thermal
and mechanical hypersensitivity. As shown in our previous report, melittin
was the most potent polypeptide in production of local inflammation as well
as ongoing pain and hypersensitivity. To further explore the peripheral mechanisms
underlying melittin-induced nociception and hypersensitivity, a single dose
of capsazepine, a blocker of thermal nociceptor transient receptor potential
vanilloid receptor 1, was treated s.c. prior to or after melittin administration.
The results showed that both pre- and post-treatment of capsazepine could
significantly prevent and suppress the melittin-induced ongoing nociceptive
responses and thermal hypersensitivity, but were without influencing mechanical
hypersensitivity. The present results suggest that the naturally occurring
peptidergic substances of the whole honeybee venom have various pharmacological
potencies to produce local inflammation, nociception and pain hypersensitivity
in mammals, and among the five identified reverse-phase high pressure liquid
chromatography subfractions (four polypeptides), melittin, a polypeptide occupying
over 50% of the whole honeybee venom, plays a central role in production of
local inflammation, nociception and hyperalgesia or allodynia following the
experimental honeybee's sting. Peripheral transient receptor potential vanilloid
receptor 1 is likely to be involved in melittin-produced ongoing pain and
heat hyperalgesia, but not mechanical hyperalgesia, in rats.
PMID: 16446039 [PubMed - as supplied by publisher]
| 3: Nurs Stand. 2005 Nov 2-8;20(8):22-4. |
It's all the buzz.
O'Connell
N.
Although honey has been used medicinally for thousands of years, bee products
have only recently become the subject of in depth medical research. Wound
healing products containing honey are now available. Bee venom has been used
to treat painful conditions. Propolis is a potent anti-inflammatory agent.
Broad claims have been made for royal jelly.
PMID: 16295595 [PubMed - indexed for MEDLINE]
| 4: Exp Neurol. 2005 Sep;195(1):148-60. |
Unilateral
subcutaneous bee venom but not formalin injection causes contralateral hypersensitized
wind-up and after-discharge of the spinal withdrawal reflex in anesthetized
spinal rats.
You
HJ, Arendt-Nielsen
L.
Center for Sensory-Motor Interaction (SMI), Laboratory for Experimental Pain
Research, Aalborg University, Fredrik Bajers Vej 7 D-3, DK-9220 Aalborg, Denmark.
This study aimed to investigate the effect of tonic nociception on spinal
withdrawal reflexes including (1) long lasting spontaneous responses elicited
by subcutaneous (s.c.) administration of formalin (2.5%, 50 microl) and bee
venom (BV, 0.2 mg/50 microl) into the hind paw and (2) corresponding ipsilateral
(primary) and contralateral (secondary) hypersensitivity to noxious pinch
and repetitive supra-threshold (1.5 x T) electrical stimuli at different frequencies
(3 Hz: wind-up; 20 Hz: after-discharge) in anesthetized spinal rats. Spinal
withdrawal reflexes were studied by simultaneously assessing single motor
units (SMUs) electromyographic (EMG) activities from the bilateral medial
gastrocnemius (MG) muscles. Subcutaneous formalin-induced persistent spontaneous
SMU EMG responses were in typical biphasic manner with an apparent silent
period (about 13-18 min), but in contrast, BV elicited monophasic long lasting
(about 1 h) SMU EMG responses without any resting state. The mechanically
and electrically evoked responsiveness of SMUs were enhanced significantly
by ipsilateral BV injection, whereas enhanced electrically, but not mechanically,
evoked responses (including wind-up and after-discharge) were found at the
non-injection site of the contralateral hind paw. However,
| 5: J Pharmacol Exp Ther. 2005 Sep;314(3):1353-61. Epub 2005 Jun 9. |
Tertiapin-Q
blocks recombinant and native large conductance K+ channels in a use-dependent
manner.
Kanjhan
R, Coulson
EJ, Adams
DJ, Bellingham
MC.
School of Biomedical Sciences,
Tertiapin, a short peptide from honey bee venom, has been reported to specifically
block the inwardly rectifying K(+) (Kir) channels, including G protein-coupled
inwardly rectifying potassium channel (GIRK) 1+GIRK4 heteromultimers and ROMK1
homomultimers. In the present study, the effects of a stable and functionally
similar derivative of tertiapin, tertiapin-Q, were examined on recombinant
human voltage-dependent Ca(2+)-activated large conductance K(+) channel (BK
or MaxiK; alpha-subunit or hSlo1 homomultimers) and mouse inwardly rectifying
GIRK1+GIRK2 (i.e., Kir3.1 and Kir3.2) heteromultimeric K(+) channels expressed
in Xenopus oocytes and in cultured newborn mouse dorsal root ganglion (DRG)
neurons. In two-electrode voltage-clamped oocytes, tertiapin-Q (1-100 nM)
inhibited BK-type K(+) channels in a use- and concentration-dependent manner.
We also confirmed the inhibition of recombinant GIRK1+GIRK2 heteromultimers
by tertiapin-Q, which had no effect on endogenous depolarization- and hyperpolarization-activated
currents sensitive to extracellular divalent cations (Ca(2+), Mg(2+), Zn(2+),
and Ba(2+)) in defolliculated oocytes. In voltage-clamped DRG neurons, tertiapin-Q
voltage- and use-dependently inhibited outwardly rectifying K(+) currents,
but Cs(+)-blocked hyperpolarization-activated inward currents including I(H)
were insensitive to tertiapin-Q, baclofen, barium, and zinc, suggesting absence
of functional GIRK channels in the newborn. Under current-clamp conditions,
tertiapin-Q blocked the action potential after hyperpolarization (AHP) and
increased action potential duration in DRG neurons. Taken together, these
results demonstrate that the blocking actions of tertiapin-Q are not specific
to Kir channels and that the blockade of recombinant BK channels and native
neuronal AHP currents is use-dependent. Inhibition of specific types of Kir
and voltage-dependent Ca(2+)-activated K(+) channels by tertiapin-Q at nanomolar
range via different mechanisms may have implications in pain physiology and
therapy.
| 6: Toxicon. 2005 Jul;46(1):39-45. |
Bee venom
induces apoptosis through caspase-3 activation in synovial fibroblasts of
patients with rheumatoid arthritis.
Hong SJ, Rim GS, Yang HI, Yin CS, Koh HG, Jang MH, Kim CJ, Choe BK, Chung JH.
Department of Internal Medicine,
College of Medicine, Pochon CHA University, 351 Yatap-dong, Bundang-gu, Sungnam-si,
Kyonggi-do 463-712, South Korea.
Bee venom (BV) has been used traditionally for the control of pain and inflammation
in various chronic inflammatory diseases, including rheumatoid arthritis (RA)
in Oriental medicine. However, it is still unclear how BV exerts its beneficial
effects on the clinical course of RA patients. To investigate the effect of
BV on the treatment of rheumatoid synovitis, we examined the inhibition of
cell growth and induction of apoptosis in human rheumatoid synovial fibroblasts.
Rheumatoid synovial fibroblasts were surgically obtained from patients with
RA. Cell proliferation and viability were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT) assay. The apoptosis of synovial cells treated with 10 microg/ml
BV for 24 h was identified by 4,6-diamidino-2-phenylindole (DAPI) staining,
terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL)
assay, DNA fragmentation assay, RT-PCR, and Western blot analysis. It was
demonstrated that rheumatoid synovial cells treated with 10 microg/ml BV for
24 h exhibited apoptotic features and fragmentation of DNA. In addition, BV
induces apoptosis in rheumatoid synovial cells through a decrease in BCL2
expression and an increase in BAX and caspase-3 (CASP3) expression. It is
suggested that BV inhibits the proliferation of rheumatoid synovial cells
through induction of apoptosis by CASP3 activation.
PMID: 15922390 [PubMed - indexed for MEDLINE]
| 7: Neurosci Lett. 2005 Jun 10-17;381(1-2):194-8. Epub 2005 Mar 2. |
Activation
of spinal extracellular signaling-regulated kinases by intraplantar melittin
injection.
Yu YQ, Chen
J.
Pain Research Center, Institute of Neuroscience, Fourth Military Medical University,
17 West Chang-le Road, Xi'an 710032, PR China.
Intraplantar injection of melittin, a major toxic peptide of whole bee venom,
has been proved to cause alteration in both behavioral and spinal neuronal
responses in rats. To see whether extracellular signaling-regulated kinases
(ERK) in the spinal cord dorsal horn are activated and involved in induction
and maintenance of persistent ongoing nociception, pain hypersensitivity and
inflammation, three doses of U0126 (1,4-diamino-2,3-dicyano-1, 4-bis-[o-aminophenylmercapto]butadiene),
a widely used specific MAP kinase kinase (MEK) inhibitor, were administered
through chronic intrathecal catheterization prior to or after intraplantar
injection of melittin. We found that: (1) the induction of melittin-induced
persistent spontaneous nociception (PSN), mechanical and heat hypersensitivity
could be suppressed by U0126 in a dose-related manner; (2) specific inhibition
of ERK pathway suppressed the maintenance of melittin-induced PSN and heat
hypersensitivity, while established mechanical hypersensitivity could not
be reversed; and (3) intrathecal administration of U0126 had no effects on
peripheral inflammation induced by melittin. This result suggests that spinal
ERK pathway might be a common factor involved in inducing and maintaining
pathophysiological processes of ongoing pain and heat hyperalgesia, while
the role of ERK pathway in generation of the mechanical hypersensitivity is
not consistent and remains to be further clarified.
PMID: 15882816 [PubMed - indexed for MEDLINE]
| 8: Brain Res. 2005 May 10;1043(1-2):231-5. |
Evidence
for peripherally antinociceptive action of propofol in rats: behavioral and
spinal neuronal responses to subcutaneous bee venom.
Sun
YY, Li KC, Chen
J.
Pain Research Center, Institute of Neuroscience, Fourth Military Medical University,
17 West Chang-le Road, Xi'an 710032, PR China.
In the present study, behavioral and in vivo electrophysiological methods
were used to examine the peripheral effects of propofol on tonic ongoing pain-related
responses produced by subcutaneous bee venom-induced inflammatory pain state.
Local administration of 0.5 microg propofol produced significant suppression
of the well-established ongoing pain responses in both conscious rats and
dorsal horn nociceptive neurons. The locally antinociceptive action of propofol
is not caused by systemic effect, because contralateral administration of
the same dose of drug did not produce any effect. This result indicates that
besides central actions, propofol has peripherally antinociceptive action
as well.
PMID: 15862538 [PubMed - indexed for MEDLINE]
| 9: Evid Based Complement Alternat Med. 2005 Mar;2(1):79-84. |
An Overview
of Bee Venom Acupuncture in the Treatment of Arthritis.
Lee
JD, Park
HJ, Chae
Y, Lim
S.
Bee venom acupuncture (BVA), as a kind of herbal acupuncture, exerts not only
pharmacological actions from the bioactive compounds isolated from bee venom
but also a mechanical function from acupuncture stimulation. BVA is growing
in popularity, especially in Korea, and is used primarily for pain relief
in many kinds of diseases. We aimed to summarize and evaluate the available
evidence of BVA for rheumatoid arthritis and osteoarthritis. Computerized
literature searches for experimental studies and clinical trials of BVA for
arthritis were performed on the databases from PUBMED, EMBASE and the Cochrane
Library. In addition, two leading Korean journals (The Journal of Korean Society
for Acupuncture and Moxibustion and The Journal of Korean Oriental Medicine)
were searched for relevant studies. The search revealed 67 studies, 15 of
which met our criteria. The anti-inflammation and analgesic actions of BVA
were proved in various kinds of animal arthritic models. Two randomized controlled
trials and three uncontrolled clinical trials showed that BVA was effective
in the treatment of arthritis. It is highly likely that the effectiveness
of BVA for arthritis is a promising area of future research. However, there
is limited evidence demonstrating the efficacy of BVA in arthritis. Rigorous
trials with large sample size and adequate design are needed to define the
role of BVA for these indications. In addition, studies on the optimal dosage
and concentration of BVA are recommended for future trials.
PMID: 15841281 [PubMed - as supplied by publisher]
| 10: Neurosci Lett. 2005 Feb 25;375(1):42-6. Epub 2004 Nov 19. |
Changes of
5-HT receptor subtype mRNAs in rat dorsal root ganglion by bee venom-induced
inflammatory pain.
Liu XY, Wu SX, Wang YY, Wang W, Zhou L, Li YQ.
Department of Anatomy and K.K.
Leung Brain Research Centre, The Fourth Military Medical University, Xi'an
710032, PR China.
The reverse transcriptase polymerase chain reaction (RT-PCR) technique was
used to examine the changes of the expression of 5-hydroxytryptamine (5-HT)
receptors in the rat lumbar dorsal root ganglion (DRG) following subcutaneous
bee venom (BV) injection into the plantar surface of the unilateral hindpaw.
In the DRG ipsilateral to the BV injection, significant increase of mRNA levels
of 5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(3) receptor subtypes were observed
at 1 and 4h after the BV injection, while increase of 5-HT(
| 11: Pharmacol Biochem Behav. 2005 Jan;80(1):181-7. Epub 2004 Nov 26. |
Water soluble
fraction (<10 kDa) from bee venom reduces visceral pain behavior through
spinal alpha 2-adrenergic activity in mice.
Kwon YB, Ham TW, Kim HW, Roh DH, Yoon SY, Han HJ, Yang IS, Kim KW, Beitz AJ, Lee JH.
Department of Pharmacology, Institute
for Medical Science, Chonbuk National University Medical School, Chonju, South
Korea.
We have previously shown that subcutaneous bee venom (BV) injection reduces
visceral pain behavior in mice, but it is not clear which constituent of BV
is responsible for its antinociceptive effect. In the present study, we now
demonstrate that a water-soluble subfraction of BV (BVA) reproduces the antinociceptive
effect of BV in acetic acid-induced visceral pain model. We further evaluated
three different BVA subfractions that were separated by molecular weight,
and found that only the BVAF3 subfraction (a molecular weight of <10 kDa)
produced a significant antinociceptive effect on abdominal stretches and suppressed
visceral pain-induced spinal cord Fos expression. Injection of melittin (MEL),
a major constituent of BVAF3, also produced a visceral antinociception. However,
melittin's antinociception was completely blocked by boiling for 10 min at
100 degrees C, while boiling either whole BV or BVAF3 did not prevent their
antinociception. The antinociceptive effect of BVAF3 was completely blocked
by intrathecal pretreatment with the alpha2-adrenoceptor antagonist, yohimbine
(YOH), while intrathecal pretreatment with the opioid antagonist, naloxone
(NAL) or the serotonin antagonist, methysergide, had no effect. These data
demonstrate that BVAF3 is responsible for the visceral antinociception of
whole BV and further suggest that this effect is mediated in part by spinal
alpha2-adrenergic activity.
PMID: 15652394 [PubMed - indexed for MEDLINE]
| 12: Pharmacol Res. 2005 Feb;51(2):183-8. |
Antinociceptive
mechanisms associated with diluted bee venom acupuncture (apipuncture) in
the rat formalin test: involvement of descending adrenergic and serotonergic
pathways.
Kim
HW, Kwon
YB, Han
HJ, Yang
IS, Beitz
AJ, Lee
JH.
Department of Veterinary Physiology, College of Veterinary Medicine and School
of Agricultural Biotechnology, Seoul National University, San 56-1, Shilim-dong,
Kwanak-gu, Seoul 151-742, South Korea.
In a previous report, subcutaneous injection of diluted bee venom (dBV) into
a specific acupuncture point (Zusanli, ST36), a procedure termed apipuncture,
was shown to produce an antinociceptive effect in the rat formalin pain model.
However, the central antinociceptive mechanisms responsible for this effect
have not been established. Traditional acupuncture-induced antinociception
is considered to be mediated by activation of the descending pain inhibitory
system (DPIS) including initiation of its opioidergic, adrenergic and serotonergic
components. The purpose of the present study was to investigate whether the
antinociceptive effect of apipuncture is also mediated by the DPIS. Behavioral
experiments verified that apipuncture significantly reduces licking behavior
in the late phase of formalin test in rats. This antinociceptive effect of
apipuncture was not modified by intrathecal pretreatment with naltrexone (a
non-selective opioid receptor antagonist), prazosin (an alpha1 adrenoceptor
antagonist) or propranolol (an beta adrenoceptor antagonist). In contrast,
intrathecally injected idazoxan (an alpha2 adrenoceptor antagonist) or intrathecal
methysergide (a serotonin receptor antagonist) significantly reversed apipuncture-induced
antinociception. These results suggest that apipuncture-induced antinociception
is produced by activation of alpha2 adrenergic and serotonergic components
of the DPIS.
PMID: 15629266 [PubMed - indexed for MEDLINE]
| 13: Am J Chin Med. 2004;32(3):361-7. |
Anti-inflammatory
effect of bee venom on type II collagen-induced arthritis.
Lee JD, Kim SY, Kim TW, Lee SH, Yang HI, Lee DI, Lee YH.
Research Group of Pain and Neuroscience
in Vision 2000 Project East-West Medical Research Institute, Kyung Hee University,
Seoul, Korea. ljdacu@khmc.or.kr
Bee venom (BV) has been used to relieve pain and reduce inflammation in traditional
Oriental medicine, especially in chronic inflammatory diseases such as rheumatoid
arthritis (RA). We previously reported that the BV injection into a traditional
acupuncture point (Zusanli) reduced arthritis-associated edema and nociceptive
responses in Freund's adjuvant-induced arthritis in rats (Kwon et al., 2001).
This study was designed to evaluate the anti-inflammatory and anti-cytokine
effect of BV on a murine type-II collagen-induced arthritis (CIA) model. Male
mice were immunized by spontaneous injection of 100 microg of an emulsion
of bovine type-II collagen and complete Freund's adjuvant (CFA), with a booster
injection after 2 weeks. In the experimental group, 0.1 ml BV was injected
at acupuncture point (Zusanli) near both knees twice a week for a total of
5 times. In the control group, normal saline was injected at the same frequencies.
These injections began 5 weeks after the first collagen injection. Starting
the 3rd week after the first collagen injection, we examined limb swelling
and severity of arthritis twice a week. At 8 weeks, mice were sacrificed and
synovial tissue was examined with the light microscope and serum cytokines
(IL-1beta and TNF-alpha) were measured by ELISA. The incidence of arthritis,
the mean arthritis index and the number of arthritic limbs were significantly
lower in the treatment compared to the control group (63% versus 75%, 3.4%
versus 8.5%, 23% versus 75%, respectively). Among the serum proinflammatory
cytokines, the production of TNF-alpha in the BV group was suppressed compared
to the control group (59 +/- 4.5 versus 99.5 +/- 6.5, p < 0.05), but IL-1beta
was not suppressed. The examination of the histopathology of the joints of
murine CIA showed decreased inflammation signs and less lymphocyte infiltration
after BV acupuncture therapy. Acupuncture therapy with BV suppressed the development
of arthritis and caused inhibition of the immune responses in type-II collagen-induced
arthritis.
PMID: 15344419 [PubMed - indexed for MEDLINE]
| 14: J Pain. 2004 Aug;5(6):297-303. |
Acupoint
stimulation with diluted bee venom (apipuncture) alleviates thermal hyperalgesia
in a rodent neuropathic pain model: involvement of spinal alpha 2-adrenoceptors.
Roh DH, Kwon YB, Kim HW, Ham TW, Yoon SY, Kang SY, Han HJ, Lee HJ, Beitz AJ, Lee JH.
Department of Veterinary Physiology,
College of Veterinary Medicine, Seoul National University, South Korea.
Chemical acupuncture with diluted bee venom (DBV), termed apipuncture, has
been traditionally used in oriental medicine to treat several inflammatory
diseases and chronic pain conditions. In the present study we investigated
the potential antihyperalgesic and antiallodynic effects of apipuncture in
a rat neuropathic pain model. DBV (0.25 mg/kg, subcutaneous) was injected
into the Zusanli acupoint 2 weeks after chronic constrictive injury (CCI)
of the sciatic nerve. Between 5 and 45 minutes after DBV injection, we observed
a significant reduction in the thermal hyperalgesia induced by CCI, but apipuncture
failed to reduce CCI-induced mechanical allodynia. We subsequently examined
whether this antihyperalgesic effect of apipuncture was related to the activation
of spinal opioid receptors and/or alpha2-adrenoceptors. Intrathecal pretreatment
with naloxone (10 microg/rat), an opioid receptor antagonist, did not reverse
the antihyperalgesic effect of apipuncture, whereas pretreatment with idazoxan
(40 microg/rat), an alpha2-adrenoceptor antagonist, completely blocked the
effect of apipuncture. These results indicate that DBV-induced apipuncture
significantly reduces the thermal hyperalgesia generated by CCI and also suggest
that this antihyperalgesic effect is dependent on the activation of alpha2-adrenoceptors,
but not opioid receptors, in the spinal cord. PERSPECTIVE: The antinociceptive
effect of apipuncture was evaluated in a rodent neuropathic pain model. The
relieving effect of apipuncture on thermal hyperalgesia was found to be mediated
by spinal alpha2-adrenoceptors, but not opioid receptors. These data suggest
that apipuncture might be an effective alternative therapy for patients with
painful peripheral neuropathy, especially for those who are poorly responsive
to opioid analgesics.
PMID: 15336634 [PubMed - indexed for MEDLINE]
| 15: Neuroreport. 2004 Aug 6;15(11):1745-9. |
Melittin
selectively activates capsaicin-sensitive primary afferent fibers.
Shin
HK, Kim
JH.
Department of Physiology, College of Medicine, Hanyang University, 17 Haengdang-Dong,
Seongdong-Gu, Seoul 133-791, Korea. shinhg@hanyang.ac.kr
Whole bee venom (WBV)-induced pain model has been reported to be very useful
for the study of pain. However, the major constituent responsible for the
production of pain by WBV is not apparent. Intraplantar injection of WBV and
melittin dramatically reduced mechanical threshold, and increased flinchings
and paw thickness. In behavioral experiments, capsaicin pretreatment almost
completely prevented WBV- and melittin-induced reduction of mechanical threshold
and flinchings. Intraplantar injection of melittin increased discharge rate
of dorsal horn neurons only with C fiber input from peripheral receptive field,
which was completely blocked by topical application of capsaicin to sciatic
nerve. These results suggest that both melittin and WBV induce nociceptive
responses by selective activation of capsaicin-sensitive afferent fibers.
PMID: 15257140 [PubMed - indexed for MEDLINE]
| 16: Neuroscience. 2004;126(3):753-62. |
Altered pain-related
behaviors and spinal neuronal responses produced by s.c. injection of melittin
in rats.
Li KC, Chen
J.
Pain Research Center, Institute of Neuroscience, Fourth Military Medical University,
17 West Chang-le Road, Xi'an 710032, P.R. People's Republic of China.
Recently, we have reported that following s.c. injection of a solution containing
the whole bee-venom (BV; Apis mellifera), into one hind paw of a rat, the
experimentally produced honeybee's sting, the animal shows altered pain-related
behaviors and inflammation relevant to pathological pain state. To see whether
melittin, the major (over 50%) toxic component of the BV, is responsible for
the above abnormal pain behavioral changes, the present study was designed
to investigate the effects of s.c. melittin on either nociceptive behaviors
in conscious rats or spinal dorsal horn neuronal responses in anesthetized
rats. In the behavioral surveys, s.c. injection of three doses of both melittin
(5, 25 and 50 microg) and BV (10, 50 and 100 microg) into the posterior surface
of one hind paw of rats produced an immediate tonic nociceptive response displaying
as persistent spontaneous paw flinching reflex. Similar to the BV test, the
melittin response was also monophasic and dose-dependent in terms of both
intensity and time course. As an accompanied consequence, both heat and mechanical
hypersensitivity (hyperalgesia and allodynia) and inflammatory responses (paw
swelling and plasma extravasation) were induced by s.c. melittin injections.
In the electrophysiological recordings, s.c. injection of the same three doses
of melittin into the cutaneous receptive field produced an immediate, dose-dependent
increase in spontaneous spike discharges of spinal dorsal horn wide-dynamic-range
(WDR) neurons which are believed to be responsible for the spinally-organized
nociceptive flexion reflex. The melittin-induced ongoing spike responses are
similar to the behavioral flinching reflex in terms of both duration and frequency.
Furthermore, the responsiveness of the WDR neurons to both heat (42 degrees
C, 45 degrees C, 47 degrees C and 49 degrees C) and mechanical (brush, pressure
and pinch) stimuli was significantly enhanced by s.c. injection of melittin
shown as a leftward shift of the stimulus-response functional curves. Taken
together, the present results suggest that melittin, the major toxin of the
whole BV, is likely to be responsible for production of the long-term spinal
neuronal changes as well as persistent spontaneous nociception, heat/mechanical
hypersensitivity and inflammatory responses that are produced by experimental
honeybee's sting.
PMID: 15183523 [PubMed - indexed for MEDLINE]
| 17: Sheng Li Xue Bao. 2004 Apr 25;56(2):178-82. |
Age-related
changes in deterministic behaviors of nociceptive firing of rat dorsal horn
neurons.
Zheng
JH, Feng
W, Jian
Z, Chen
J.
Pain Research Center, Institute of Neuroscience, K. K. Leung Brain Research
Centre, The Fourth Military Medical University, Xi'an 710032, China.
To demonstrate the age-related changes in the dynamics of the nociceptive
discharge of dorsal horn nociceptive neurons, the nonlinear prediction method
was used to quantify the degree of deterministic behavior within the interspike
interval series of tissue injury-induced firing of spinal nociceptive neurons
in anesthetized adult young (3-4 months) and aged (>22 months) rats. Subcutaneous
bee venom injection induced long-term discharge of spinal wide dynamic range
(WDR) neurons in both groups. However, the nociceptive discharge of single
WDR neurons in the aged group showed higher determinism when compared with
the adult young rats. This result suggests that the dynamics of single nociceptive
neurons may not remain constant throughout the life span, and this age-associated
change may be an underlying mechanism for various pain manifestations in the
elderly population.
PMID: 15127127 [PubMed - indexed for MEDLINE]
| 18: Brain Res. 2004 Mar 19;1001(1-2):143-9. |
Complexity
of tissue injury-induced nociceptive discharge of dorsal horn wide dynamic
range neurons in the rat, correlation with the effect of systemic morphine.
Zheng
JH, Chen
J, Arendt-Nielsen
L.
Pain Research Center (PRC), Institute of Neuroscience, The Fourth Military
Medical University, Xi'an 710032, PR China.
Persistent discharge of wide dynamic range (WDR) neurons was recorded from
lumbar dorsal horn of anesthetized rats following subcutaneous bee venom injection
into the receptive field. To quantitatively describe the complexity of this
nociceptive activity, we computed the approximate entropy (ApEn) for each
sampled interspike interval (ISI) series. A larger value of ApEn indicates
higher complexity or less regularity and vice versa. The ApEn value varied
across different WDR neurons tested, and for each neuron the ApEn remained
constant through the 1-h discharge though the average ISI of the sampled data
increased progressively with time (16 neurons). A low dose of intravenous
morphine (0.3 mg/kg) depressed the activity of WDR neurons differentially,
and the degree of this inhibition showed a significant correlation with the
value of ApEn (P<0.001, 27 neurons, Spearman's correlation test). The present
results suggest that the complexity feature of WDR neurons is various under
tissue injury state, and for each single WDR neuron the complexity feature
is relatively independent of the strength of peripheral noxious input and
cannot be fully described in terms of average firing rate. Moreover, the response
of the nociceptive discharge to analgesics may be related to the nonlinear
dynamics feature of nociceptive neurons, which can be quantitatively characterized
by the degree of complexity.
PMID: 14972663 [PubMed - indexed for MEDLINE]
| 19: Neurosignals. 2003 Nov-Dec;12(6):292-301. |
Differential
roles of spinal protein kinases C and a in development of primary heat and
mechanical hypersensitivity induced by subcutaneous bee venom chemical injury
in the rat.
Li KC, Chen
J.
Pain Research Center (PRC), Institute of Neuroscience, Fourth Military Medical
University, Xi'an, China.
It has been demonstrated that subcutaneous injection of bee venom (BV) can
produce different types of pain and hypersensitivity including persistent
spontaneous nociception (PSN), primary heat and mechanical hypersensitivity
(hyperalgesia) and mirror-image heat (MIH) hypersensitivity in an individual
animal, and the changes of spinal neurons are likely to be responsible for
the production of these pain-related behaviors. In this study, we examined
the roles of spinal protein kinase C (PKC) and protein kinase A (PKA) in the
BV-induced different types of pain and hypersensitivity in conscious rats.
We found that: (1). BV-induced primary heat hypersensitivity could be blocked
by intrathecal pre- or posttreatment with a PKC inhibitor, chelerythrine chloride
(CH), while a PKA inhibitor, N-(2-[P-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide
hydrochloride (H89), had no effect. (2). BV-induced primary mechanical hypersensitivity
could be blocked by pre- or posttreatment with H89, whereas CH had no effect.
(3). Both pre- and posttreatment with H89 produced suppressive effects on
both induction and maintenance of the BV-induced PSN and MIH hypersensitivity.
Based on the present findings, we proposed that spinal PKC might be activated
during the central processes of primary heat hypersensitivity, while spinal
PKA is likely to be involved in primary mechanical hypersensitivity induced
by subcutaneous BV chemical injury. Taken together with our previous report
however, spinal PKC and PKA are likely to be simultaneously involved in the
central processes of both PSN and MIH hypersensitivity. Copyright 2003 S.
Karger AG, Basel
PMID: 14739559 [PubMed - indexed for MEDLINE]
| 20: Pain. 2003 Nov;106(1-2):135-42. |
5-hydroxytryptamine1A
receptor is involved in the bee venom induced inflammatory pain.
Wang W, Wu SX, Wang YY, Liu XY, Li YQ.
Department of Anatomy and K.K.
Leung Brain Research Centre, The Fourth Military Medical University, 17 West
Chang'le Road, Xi'an 710032, People's Republic of China.
Injection of bee venom into one hindpaw of rat can elicit acute inflammation
together with spontaneous pain, heat hyperalgesia and mechanical hyperalgesia/allodynia
in the injected paw. 5-hydroxytryptamine (5-HT)1A receptor is the predominant
receptor subtype in the spinal dorsal horn mediating the function of 5-HT
in nociception. The goal of the present study is to assess the role of 5-HT1A
receptor in the pain associated with the bee venom induced inflammation. Here
we showed that 1 or 4 h after a subcutaneous bee venom challenge, expression
of 5-HT1A receptor mRNA in the ipsilateral lumbar spinal cord increased significantly
by 80.94 or 37.86%, respectively. Antisense oligodeoxynucleotide knockdown
of spinal 5-HT1A receptor attenuated spontaneous pain and reversed heat hyperalgesia
in rats injected with bee venom. Thus, the present data suggest a facilitating
role for 5-HT1A receptor in bee venom induced inflammatory pain.
PMID: 14581120 [PubMed - indexed for MEDLINE]
| 21: Sheng Li Xue Bao. 2003 Oct 25;55(5):516-24. |
Effects of
intravenous Injections Paederiae and Stauntonia on spontaneous pain, hyperalgesia
and inflammation induced by cutaneous chemical tissue injury in the rat.
Peng
XL, Gao
XL, Chen
J, Huang
X, Chen
HS.
Pain Research Center, Institute of Neuroscience, The Fourth Military Medical
University, Xi' an 710032.
To study whether commercial traditional Chinese medicinal preparations Injection
Paederiae (IP) or Injection Stauntonia (IS) has anti-nociceptive and/or anti-inflammatory
effects, we used two persistent pain models (bee venom and formalin test)
to evaluate the systemic effects of IP or IS on the chemical tissue injury-induced
persistent spontaneous pain-related responses (PSPR), primary thermal/mechanical
hyperalgesia and inflammation in conscious rats. Injection of bee venom (BV,
0.1 mg, 50 microl) into the plantar surface of one hind paw resulted in not
only a 1-h monophasic PSPR such as flinching reflex in the injected paw and
a subsequent period of 3-4 days primary heat and mechanical hyperalgesia,
but also a marked sign of inflammation, including redness and swelling of
the plantar surface in the injected paw. Intraplantar injection of formalin
produced two phases of PSPR as reported previously. Systemic pre-treatment
with three doses of IP (0.32, 1.6 and 9.0 ml/kg, 500%) or IS (0.32, 1.6 and
9.0 ml/kg, 250%) produced a dose-dependent suppression of the BV- or formalin-induced
flinching reflex of 1 h time course as compared with the saline control group.
Post-treatment with IP or IS 5 min after BV injection also produced a significant
suppression of the flinching reflex in both BV test and formalin test respectively,
as compared with the control group. However, neither pre- nor post-treatment
with IP or IS produced any significantly suppressive effect on the BV-induced
primary heat and mechanical hyperalgesia and inflammation. The analgesia produced
by IP or IS was not mediated by the endogenous opioid receptors since naloxone,
a non-selective opioid receptor antagonist, had no reversal effect on the
IP and IS-produced analgesia in the BV-induced PSPR. Our present results suggest
that IP or IS might prevent and relieve clinical persistent spontaneous pain,
but without any anti-nociceptive and anti-inflammatory effects on the primary
heat hyperalgesia, mechanical hyperalgesia, as well as inflammatory responses.
The BV test might be a useful model of pain to evaluate and screen anti-nociceptive
and anti-inflammatory effects of certain compounds of the Chinese medicinal
herbs on the pathological origins of pain.
PMID: 14566397 [PubMed - indexed for MEDLINE]
| 22: Neuroscience. 2003;121(2):459-72. |
Differential
antinociceptive effects induced by a selective cyclooxygenase-2 inhibitor
(SC-236) on dorsal horn neurons and spinal withdrawal reflexes in anesthetized
spinal rats.
You
HJ, Morch
CD, Chen
J, Arendt-Nielsen
L.
Center for Sensory-Motor Interaction, Laboratory for Experimental Pain Research,
Aalborg University, Fredrik Bajers Vej 7D-3, DK-9220, Aalborg, Denmark. lan@smi.auc.dk
The aim of present study was to examine the effect of a selective cyclooxygenase-2
(COX-2) inhibitor SC-236 (4 mg/kg) on the simultaneous responsiveness of spinal
wide-dynamic range (WDR) neurons and single motor units (SMUs) from gastrocnemius
soleus muscles to mechanical stimuli (pressure and pinch) and repeated suprathreshold
(1.5xT, the intensity threshold) electrical stimuli with different frequencies
(3 Hz, 20 Hz) under normal conditions and bee venom (BV, 0.2 mg/50 microl)-induced
inflammation and central sensitization. During normal conditions, the responses
of SMUs, but not WDR neurons, to mechanical and repeated electrical stimuli
(3 Hz, wind-up) were depressed by systemic administration of SC-236 as well
as its vehicle (100% dimethyl sulfoxide (DMSO)). The after-discharges of both
the WDR neurons and the simultaneously recorded SMUs after electrical stimuli
with 20 Hz were markedly depressed only by SC-236, indicating that the mechanisms
underlying the generation of the C-fiber mediated late responses and the after-discharges
may be different. The enhanced responsiveness of both WDR neurons and SMUs
to mechanical pressure stimuli (allodynia) and pinch stimuli (hyperalgesia)
in the BV experiments was apparently depressed by SC-236, but not its vehicle.
For electrical stimulation, the enhanced late responses and after-discharges,
but not early responses, of both the WDR neurons and the simultaneously recorded
SMUs were markedly depressed only by SC-236. This indicates that different
central pharmacological mechanisms underlie the generation of these enhanced
early, late responses, and after-discharges during BV-induced inflammation.
The data suggest that the COX-2 inhibitor SC-236 apparently depress the activities
of both spinal cord dorsal horn neuron and spinal withdrawal reflex during
BV-induced sensitization, indicating that COX-2 plays an important role in
the maintenance of central sensitization.
PMID: 14522004 [PubMed - indexed for MEDLINE]
| 23: Brain Res. 2003 Aug 15;981(1-2):12-22. |
Role of central
NMDA versus non-NMDA receptor in spinal withdrawal reflex in spinal anesthetized
rats under normal and hyperexcitable conditions.
You
HJ, Morch
CD, Chen
J, Arendt-Nielsen
L.
Center for Sensory-Motor Interaction (SMI), Laboratory for Experimental Pain
Research, Aalborg University, Fredrik Bajers Vej 7, Building D-3, DK-9220
Aalborg, Denmark.
The present study aimed to investigate the role of central N-methyl-D-aspartate
(NMDA) and non-NMDA receptors in the spinal withdrawal reflex assessed by
recording single motor unit (SMU) electromyogram (EMG) response to peripheral
mechanical (pressure, pinch) stimuli and repeated electrical stimuli at 3
and 20 Hz. During normal conditions, intrathecal administration of MK-801
and CNQX apparently depressed mechanically and electrically (3 Hz) evoked
EMG responses in a dose-dependent manner (10, 20 and 40 nmol in 10 microl).
In contrast, the after-discharges to 20 Hz electrical stimuli were suppressed
only by CNQX treatment, not by MK-801 treatment. This indicates that the central
mechanisms underlying the different frequencies of electrically evoked withdrawal
reflex may be different. During peripheral bee venom (BV, 0.2 mg/50 microl)
induced inflammation and central sensitization, the enhanced SMU EMG responses
including after-discharges to pinch stimuli and 3 Hz electrical stimuli were
depressed significantly by treatments with both MK-801 and CNQX. However,
the enhanced SMU activities to innocuous pressure stimuli were depressed only
by treatment with CNQX. Likewise, enhanced long lasting after-discharges elicited
by 20 Hz electrical stimuli were also only depressed by CNQX, indicating that
different central mechanisms are involved in the persistent hyperexcitability
during BV-induced inflammation. The data suggest that both central NMDA and
non-NMDA receptors play important roles in the transmission of nociceptive
information under normal conditions. In BV-induced inflammation, however,
central non-NMDA receptors, but not NMDA receptors, play a pivotal role in
the generation of persistent hyperexcitability to mechanical and electrical
stimuli at different frequencies (3 Hz, 20 Hz).
PMID: 12885421 [PubMed - indexed for MEDLINE]
| 24: Arch Pharm Res. 2003 May;26(5):383-8. |
Inhibition of COX-2
activity and proinflammatory cytokines (TNF-alpha and IL-1beta) production
by water-soluble sub-fractionated parts from bee (Apis mellifera) venom.
Nam KW, Je KH, Lee JH, Han HJ, Lee HJ, Kang SK, Mar W.
Natural Products Research Institute,
Seoul National University, Seoul 110-460, Korea.
Bee venom is used as a traditional medicine for treatment of arthritis. The
anti-inflammatory activity of the n-hexane, ethyl acetate, and aqueous partitions
from bee venom (Apis mellifera) was studied using cyclooxygenase (COX) activity
and pro-inflammatory cytokines (TNF-alpha and IL-1beta) production, in vitro.
COX-2 is involved in the production of prostaglandins that mediate pain and
support the inflammatory process. The aqueous partition of bee venom showed
strong dose-dependent inhibitory effects on COX-2 activity (IC50 = 13.1 microg/mL),
but did not inhibit COX-1 activity. The aqueous partition was subfractionated
into three parts by molecular weight differences, namely, B-F1 (above 20 KDa),
B-F2 (between 10 KDa and 20 KDa) and B-F3 (below 10 KDa). B-F2 and B-F3 strongly
inhibited COX-2 activity and COX-2 mRNA expression in a dose-dependent manner,
without revealing cytotoxic effects. TNF-alpha and IL-1beta, are potent pro-inflammatory
cytokines and are early indicators of the inflammatory process. We also investigated
the effects of three subfractions on TNF-alpha and IL-1beta production using
ELISA method. All three subfractions, B-F1, B-F2 and B-F3, inhibited TNF-alpha
and IL-1beta production. These results suggest the pharmacological activities
of bee venom on anti-inflammatory process include the inhibition of COX-2
expression and the blocking of pro-inflammatory cytokines (TNF-alpha, and
IL-1beta) production.
PMID: 12785734 [PubMed - indexed for MEDLINE]
| 25: Anesthesiology. 2003 May;98(5):1231-6. |
Supraspinal
contribution to development of both tonic nociception and referred mirror
hyperalgesia: a comparative study between formalin test and bee venom test
in the rat.
Chen
HS, Li MM, Shi
J, Chen
J.
Pain Research Center, Institute of Neuroscience, The Fourth Military Medical
University, Xi'an, China.
BACKGROUND: The roles of descending facilitatory pathway from the rostral
medial medulla (RMM) in development of persistent spontaneous nociception
and hyperalgesia were evaluated in the bee venom (BV) test and the formalin
test. METHODS: Bilateral lesions of the RMM with ibotenic acid, a soma-selective
neurotoxin, were performed to study their effects on the spontaneous pain-related
behaviors and hyperalgesia, which were determined by counting the number of
flinching reflex per 5 min (1 h) and by measuring paw withdrawal thermal latency
(PWTL) and mechanical threshold (PWMT) to radiant heat and von-Frey filaments
to both hind paws in conscious rats, respectively. RESULTS: 1) Bilateral lesions
of the RMM produced a similarly significant inhibition of persistent spontaneous
flinching reflexes in the BV test and the formalin test; however, the inhibitory
effect occurred in the late 50 min (11-60 min), but not the first 10 min (0-10
min) following intraplantar injection of either BV or formalin. 2) Bilateral
lesions of the RMM prevented the development of the BV-induced referred mirror
heat hyperalgesia occurred in the noninjected paw, but had no effect on the
primary heat and mechanical hyperalgesia occurred in the injected paw. CONCLUSIONS:
The present results provide a new line of behavioral evidence that tonic activation
of descending facilitatory pathway contributes to the establishment of 1)
the BV and formalin-induced persistent spontaneous nociception; and 2) the
BV-induced referred mirror heat hyperalgesia and the central sensitization,
but not the primary heat and mechanical hyperalgesia.
PMID: 12717146 [PubMed - indexed for MEDLINE]
| 26: J Vet Med Sci. 2003 Mar;65(3):349-55. |
Acupoint
stimulation using bee venom attenuates formalin-induced pain behavior and
spinal cord fos expression in rats.
Kim HW, Kwon YB, Ham TW, Roh DH, Yoon SY, Lee HJ, Han HJ, Yang IS, Beitz AJ, Lee JH.
Department of Veterinary Physiology,
College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul
National University, Seoul, South Korea.
In two previous reports, we have demonstrated that injection of bee venom
(BV) into an acupoint produces a significant antinociceptive and anti-inflammatory
effect in both a mouse model of visceral nociception and a rat model of chronic
arthritis. The present study was designed to evaluate the potential antinociceptive
effect of BV pretreatment on formalin-induced pain behavior and it associated
spinal cord Fos expression in rats. Adult Sprague-Dawley rats were injected
with BV directly into the Zusanli (ST36) acupoint or into an arbitrary non-acupoint
located on the back. BV pretreatment into the Zusanli acupoint significantly
decreased paw-licking time in the late phase of the formalin test. In contrast,
BV injected into a non-acupoint in the back region did not suppress the paw-licking
time. In addition, BV pretreatment into the Zusanli acupoint markedly inhibited
spinal cord Fos expression induced by formalin injection. These findings indicate
that BV pretreatment into the Zusanli acupoint has an antinociceptive effect
on formalin-induced pain behavior.
PMID: 12679565 [PubMed - indexed for MEDLINE]
| 27: Neurosci Lett. 2003 Feb 13;337(3):147-50. |
A comparison
of hyperalgesia and neurogenic inflammation induced by melittin and capsaicin
in humans.
Sumikura
H, Andersen
OK, Drewes
AM, Arendt-Nielsen
L.
Center for Sensory-Motor Interaction (SMI), Department of Health Science and
Technology, Aalborg University, Fredrik Bajers Vej 7, Building D3, 9220, Aalborg,
Denmark. sumikura@smi.auc.dk
Melittin (a main compound of bee venom) and capsaicin were injected intradermally
in healthy human volunteers: (1) to study secondary mechanical hyperalgesia
(static hyperalgesia and dynamic hyperalgesia) around the injection site;
and (2) to correlate the sensory changes to the neurogenic inflammation assessed
by laser-doppler blood flowmetry. Melittin 50 microg and capsaicin 10 microg
induced comparable spontaneous pain and increased blood flow (neurogenic inflammation).
Intradermal injection of melittin induced regions of secondary mechanical
hyperalgesia around the injection site, however, they were not as large as
the hyperalgesia induced by capsaicin. This is the first report studying mechanical
hyperalgesia induced by melittin in humans, and the results were in agreement
with the previous observations in rats. Melittin seems to be a valuable model
to study a possible contribution of neurogenic inflammation to hyperalgesia
in humans.
PMID: 12536045 [PubMed - indexed for MEDLINE]
| 28: Neurosignals. 2002 Jul-Aug;11(4):224-30. |
C-fos antisense
oligodeoxynucleotide decreases subcutaneous bee venom injection-induced nociceptive
behavior and fos expression in the rat.
Wu SX, Wang
W, Wang
YY, Ni TS, Li YQ, Yew
DT.
Department of Anatomy, K.K. Leung Brain Research Centre, The Fourth Military
Medical University, No. 17 West Chang-le Road, Xi'an 710032, P.R. China.
Oligodeoxynucleotide complementary to c-fos mRNA was applied to characterize
its effect on the spinal cord Fos expression and relevant nociceptive behaviors
challenged by subcutaneous injection of bee venom to the rat hind paw. Nociceptive
behavioral responses (spontaneous pain and hyperalgesia) following bee venom
(0.2 mg/50 microl) injection were assessed in adult male Sprague-Dawley rats
receiving intrathecal administration of c-fos antisense oligodeoxynucleotide
(ASO, 50 microg/10 microl), sense oligodeoxynucleotide (SO, 50 microg/10 microl)
and saline (10 microl) 4 h prior to bee venom injection. The lumbar spinal
cord expression of Fos protein 2 h after bee venom injection in the ASO-,
SO- and saline-treated animals was observed by immunohistochemistry. The results
showed that pretreatment of c-fos ASO markedly reduced the flinching response
and primary thermal hyperalgesia, but without significant effects on mechanical
hyperalgesia and secondary thermal hyperalgesia. At the same time, ASO treatment
also significantly decreased the expression of Fos protein within the lumbar
region of the spinal cord ipsilateral to the injection. The results provide
further evidence that Fos protein contributes to the activation of the spinal
dorsal horn neurons and the generation and/or maintenance of spontaneous pain
and primary thermal hyperalgesia induced by subcutaneous injection of bee
venom. Copyright 2002 S. Karger AG, Basel
PMID: 12393948 [PubMed - indexed for MEDLINE]
| 29: Brain Res Bull. 2002 Sep 30;58(6):561-7. |
Differential
effect of peripheral glutamate (NMDA, non-NMDA) receptor antagonists on bee
venom-induced spontaneous nociception and sensitization.
You
HJ, Chen
J, Morch
CD, Arendt-Nielsen
L.
Center for Sensory-Motor Interaction (SMI), Laboratory for Experimental Pain
Research, Aalborg University, Aalborg, Denmark.
This study aimed to investigate the role of peripheral N-methyl-d-aspartate
(NMDA) and non-NMDA receptor on (1). spontaneous nociception and (2). on sensitization
induced by subcutaneous (s.c.) injection of bee venom (0.2mg/50 micro l) in
rats. Peripheral s.c. administration of the competitive NMDA receptor antagonist
dl-2-amino-5-phosphonovaleric acid (AP5), the non-competitive NMDA receptor
channel blocker MK-801, and the competitive non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione
(CNQX) were performed before (pre-treatment) and after (post-treatment) bee
venom-induced inflammation. Pre-treatment with AP5 (10mM, 50 micro l) and
both pre-treatment and post-treatment with MK-801 (2mM, 50 micro l) into the
same area of the bee venom injection site markedly reduced the bee venom-increased
spontaneous responses of wide-dynamic range (WDR) neuron of the spinal cord.
Post-treatment with the same dose of AP5 as well as pre-treatment and post-treatment
with CNQX (5mM, 50 micro l) did not produce any inhibitory effects. Additionally,
the role of peripheral NMDA and non-NMDA receptors on bee venom-induced mechanical
allodynia and hyperalgesia were investigated and assessed by the paw withdrawal
reflex to the innocuous and noxious mechanical stimulation. Peripheral administration
of AP5, but not CNQX, reduced mechanical allodynia and hyperalgesia. The data
suggest that the peripheral NMDA receptor, but not non-NMDA receptor, plays
a pivotal role in the bee venom-induced persistent nociception and hyperexcitability.
PMID: 12372559 [PubMed - indexed for MEDLINE]
| 30: J Comput Neurosci. 2002 Jul-Aug;13(1):23-34. |
Detection
of deterministic behavior within the tissue injury-induced persistent firing
of nociceptive neurons in the dorsal horn of the rat spinal cord.
Zheng
JH, Jian
Z, Chen
J.
Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military
Medical University, Xi'an 710032, People's Republic of China.
To unravel the temporal features of the peripheral tissue injury induced persistent
nociceptive discharge, single wide dynamic range (WDR) unit activity was recorded
extracellularly in lumbar dorsal horn of anesthetized rats and interspike
interval (ISI) series were obtained. Subcutaneous (s.c.) bee venom (BV) injection
induced persistent discharge of spinal WDR neurons and has been well established
to be a good model in evaluation of tissue injury induced pain. By applying
a more novel approach, i.e., the unstable periodic orbit (UPO) identification
method, we detected a family of significant separate UPOs (period-1, 2 and
3 orbits) within the ISI series of BV-induced nociceptive discharge, but not
spontaneous background activity of spinal WDR neuron. Furthermore, temporally
dynamic changes of UPOs at lower period-1, 2 and 3 for 4 successive time segments
within 1 h time course of WDR unit firing showed temporally dynamic changes,
i.e., new orbits with longer ISIs emerged and those with shorter ISIs vanished
with time change. By using this method we suggest that BV-induced nociceptive
discharge of spinal WDR neuron be a kind of deterministic activity and various
UPOs may play some role in temporal coding of sensory information.
PMID: 12154333 [PubMed - indexed for MEDLINE]
| 31: Pain. 2002 May;97(1-2):75-86. |
Heritability
of nociception. III. Genetic relationships among commonly used assays of nociception
and hypersensitivity.
Lariviere
WR, Wilson
SG, Laughlin
TM, Kokayeff
A, West
EE, Adhikari
SM, Wan
Y, Mogil
JS.
Department of Psychology and Neuroscience Program, University of Illinois
at Urbana-Champaign, IL 61820, USA.
We and others have previously demonstrated that nociception in the mouse is
heritable. A genetic correlation analysis of 12 common measures of nociception
among a common set of inbred strains revealed three major clusters (or 'types')
of nociception in this species. In the present study, we re-evaluated the
major types of nociception and their interrelatedness using ten additional
assays of nociception and hypersensitivity, including: three thermal assays
(tail withdrawal from 47.5 degrees C water or -15 degrees C ethanol; tail
flick from radiant heat), two chemical assays of spontaneous nociception (bee
venom test; capsaicin test) and their subsequent thermal hypersensitivity
states (including contralateral hypersensitivity in the bee venom test), a
mechanical nociceptive assay (tail-clip test), and a mechanical hypersensitivity
assay (intrathecal dynorphin). Confirming our earlier findings, the results
demonstrate distinct thermal and chemical nociceptive types. It is now clear
that mechanical hypersensitivity and thermal hypersensitivity are genetically
dissociable phenomena. Furthermore, we now see at least two distinct types
of thermal hypersensitivity: afferent-dependent, featuring a preceding significant
period of spontaneous nociceptive behavior associated with afferent neural
activity, and non-afferent-dependent. In conclusion, our latest analysis suggests
that there are at least five fundamental types of nociception and hypersensitivity:
(1) baseline thermal nociception; (2) spontaneous responses to noxious chemical
stimuli; (3) thermal hypersensitivity; (4) mechanical hypersensitivity; and
(5) afferent input-dependent hypersensitivity.
PMID: 12031781 [PubMed - indexed for MEDLINE]
| 32: Life Sci. 2002 May 31;71(2):191-204. |
The water-soluble
fraction of bee venom produces antinociceptive and anti-inflammatory effects
on rheumatoid arthritis in rats.
Kwon YB, Lee HJ, Han HJ, Mar WC, Kang SK, Yoon OB, Beitz AJ, Lee JH.
Department of Veterinary Physiology,
College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul
National University, Suwon, South Korea.
We recently demonstrated that bee venom (BV) injection into the Zusanli acupoint
produced a significantly more potent anti-inflammatory and antinociceptive
effect than injection into a non-acupoint in a Freund's adjuvant induced rheumatoid
arthritis (RA) model. However, the precise BV constituents responsible for
these antinociceptive and/or anti-inflammatory effects are not fully understood.
In order to investigate the possible role of the soluble fraction of BV in
producing the anti-arthritic actions of BV acupuncture, whole BV was extracted
into two fractions according to solubility (a water soluble fraction, BVA
and an ethylacetate soluble fraction, BVE) and the BVA fraction was further
tested.Subcutaneous BVA injection (0.9 mg/kg/day) into the Zusanli acupoint
was found to dramatically inhibit paw edema and radiological change (i.e.
new bone proliferation and soft tissue swelling) caused by Freund's adjuvant
injection. BVA treatment also reduced the increase in serum interleukin-6
caused by RA induction to levels observed in non-arthritic animals. In addition,
BVA therapy significantly reduced arthritis-induced nociceptive behaviors
(i.e. nociceptive scores for mechanical hyperalgesia and thermal hyperalgesia).
Finally, BVA treatment significantly suppressed adjuvant-induced Fos expression
in the lumbar spinal cord at 3 weeks post-adjuvant injection. In contrast,
BVE treatment (0.05 mg/kg/day) failed to show any anti-inflammatory or antinociceptive
effects on RA.The results of the present study demonstrate that BVA is the
effective fraction of whole BV responsible for the antinociception and anti-inflammatory
effects of BV acupuncture treatment. Thus it is recommended that this fraction
of BV be used for long-term treatment of RA-induced pain and inflammation.
However, further study is necessary to clarify which constituents of the BVA
fraction are directly responsible for these anti-arthritis effects.
PMID: 12031688 [PubMed - indexed for MEDLINE]
| 33: Klin Monatsbl Augenheilkd. 2001 Nov;218(11):747-50. |
[Bee sting
of the cornea - a case report]
[Article in German]
Grub
M, Mielke
J, Schlote
T.
Universitats-Augenklinik Tubingen, Abteilung I, Tubingen. matthias.grueb@med.uni-tuebingen.de
BACKGROUND: Bee stings of the cornea are very rare, though its response can
range from minimal inflammation to severe damage like lens dislocation, cataract
formation, iris atrophy, ophthalmoplegia and optic neuropathy. We report on
a patient with typical, severe findings. PATIENT: A 42-year-old patient presented
with an acute, corneal bee sting of the left eye, after he was stung only
a few hours ago. The patient suffered from pain, blurred vision and epiphora.
The left eye showed edema of the upper and lower eyelid, conjunctival hyperemia,
chemosis, striate keratitis, a purulent infiltration of the cornea above the
limbus at the 7 o'clock meridian and a massive hypopyon. Further examinations
showed regular ophthalmological findings. Vision acuity was 1,0/0,4. Under
therapy inflammation decreased quickly. One week after we could lokalize the
stinger in the depth of the corneal infiltration and it was removed surgically.
After one month the eye only showed a minimal infiltration of the cornea with
fine neovascularisations. Visual acuity was 0,8. CONCLUSION: Clinical reactions
to bee stings of the cornea are caused by toxical and immunological effects
of different components of the bee venom. These toxical and/or inflammatory
reactions can lead to severe intraocular damage. Treatment of choice is the
systemic and local application of steroids and antibiotics as well as local
therapy with antihistamins.
Publication Types:
PMID: 11731905 [PubMed - indexed for MEDLINE]
| 34: Am J Chin Med. 2001;29(2):187-99. |
The analgesic
efficacy of bee venom acupuncture for knee osteoarthritis: a comparative study
with needle acupuncture.
Kwon YB, Kim JH, Yoon JH, Lee JD, Han HJ, Mar WC, Beitz AJ, Lee JH.
Department of Veterinary Physiology,
College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul
National University, Suwon, Korea.
The aim of this investigation was to determine whether bee venom (BV) administered
directly into an acupoint was a clinically effective and safe method for relieving
the pain of patients with knee osteoarthritis (OA) as compared to traditional
needle acupuncture. We evaluated the efficacy of BV acupuncture using both
pain relief scores and computerized infrared thermography (IRT) following
4 weeks of BV acupuncture treatment. We observed that a significantly higher
proportion of subjects receiving BV acupuncture reported substantial pain
relief as compared with those receiving traditional needle acupuncture therapy.
Furthermore, the IRT score was significantly improved and paralleled the level
of pain relief.
Publication Types:
PMID: 11527062 [PubMed - indexed for MEDLINE]
| 35: Neurosci Lett. 2001 Aug 3;308(2):133-7. |
Visceral
antinociception produced by bee venom stimulation of the Zhongwan acupuncture
point in mice: role of alpha(2) adrenoceptors.
Kwon YB, Kang MS, Han HJ, Beitz AJ, Lee JH.
Department of Veterinary Physiology,
College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul
National University, Suwon 441-744, South Korea.
The goal of the present study was to determine whether bee venom (BV) injection
into the Zhongwan acupoint (CV12), compared to injection into a non-acupoint,
produced antinociception in an acetic acid-induced visceral pain model. This
was accomplished by injecting BV subcutaneously into the Zhongwan acupoint
or into a non-acupoint 30 min before intraperitoneal injection of acetic acid
in ICR mice. BV injection into the acupoint produced a dose dependent suppression
of acetic acid-induced abdominal stretches and of acetic acid-induced Fos
expression in the spinal cord and the nucleus tractus solitarii. In contrast
BV injection into the non-acupoint only produced antinociception at the highest
dose of BV tested. Naloxone pretreatment did not alter the antinociceptive
effect of BV acupoint injection on the abdominal stretch reflex. On the other
hand, pretreatment with the alpha 2-adrenoceptor antagonist, yohimbine completely
blocked the antinociceptive effect of BV acupoint injection. These results
imply that BV acupoint stimulation can produce visceral antinociception that
is associated with activation of alpha 2-adrenoceptors, but not with naloxone-sensitive
opioid receptors.
PMID: 11457577 [PubMed - indexed for MEDLINE]
| 36: Acupunct Electrother Res. 2001;26(1-2):59-68. |
Antinociceptive
effects of bee venom acupuncture (apipuncture) in rodent animal models: a
comparative study of acupoint versus non-acupoint stimulation.
Kwon YB, Kang MS, Kim HW, Ham TW, Yim YK, Jeong SH, Park DS, Choi DY, Han HJ, Beitz AJ, Lee JH.
Department of Veterinary Physiology,
College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul
National University, Suwon, South Korea.
From a clinical perspective, the alternative forms of acupoint stimulation
including electroacupuncture, moxibustion and acupressure appear to have more
potent analgesic effects than manual needle acupuncture. Bee venom (BV) injection
has also been reported to produce persistent nociceptive stimulation and to
cause neuronal activation in the spinal cord. In previous study, we observed
that BV stimulation into acupoint, namely BV acupuncture or Apipuncture, produced
more potent anti-inflammatory and antinociceptive potency in rodent arthritis
model as comparing with that of non-acupoint injection. Based on previous
report, we decided to further investigate that BV injection into an acupoint
produces antinociception as a result of its potent chemical stimulatory effect
in both abdominal stretch assay and formalin test. Different doses of BV were
injected into an acupoint or a non-acupoint 30 min prior to intraplantar formalin
injection or intraperitoneal acetic acid injection. Using the abdominal stretch
assay, we found that the high dose of BV (1:100 diluted in 20microl saline)
produced a potent antinociceptive effect irrespective of the site of BV injection.
In contrast the antinociceptive effect observed in both the writhing and formalin
tests following administration of a low dose of BV (1:1000 diluted in 20microl
saline) was significantly different between acupoint and non-acupoint sites.
BV injection into an acupoint (Zhongwan, Cv. 12) was found to produce significantly
greater antinociception than non-acupoint injection (
| 37: Neuropeptides. 2001 Feb;35(1):32-44. |
Differential
roles of spinal neurokinin 1/2 receptors in development of persistent spontaneous
nociception and hyperalgesia induced by subcutaneous bee venom injection in
the conscious rat.
Zheng
JH, Chen
J.
Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military
Medical University, Xi'an, P.R. China.
To evaluate the roles of spinal neurokinin receptors in the development of
persistent nociception and hyperalgesia to thermal and mechanical stimuli
induced by subcutaneous (s.c.) bee venom injection, effects of intrathecal
(i.t.) pre- or post-treatment with a non-selective antagonist of (NK1/2) receptors,
[D-Arg1,D-Trp7,9,Leu11] substance P (spantide), and a selective NK3 receptor
antagonist, (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methyl
acetamide (SR142801) were assessed in conscious rat. Injection of bee venom
s.c. into the plantar surface of one hind paw resulted in a pathological pain
phenomenon characterized by a 1-2 h single phase of persistent spontaneous
nociceptive behaviors (continuously flinching the injected paw) and a 72-96
h profound primary thermal and mechanical hyperalgesia in the injection site
and a secondary thermal hyperalgesia in the non-injected hindpaw. Pre-treatment
with spantide i.t. at 0.05 microg, 0.5 microg and 5 microg produced a dose-related
suppression of the bee venom-induced flinching reflex during the whole time
course and the inhibitory rate was 24 +/- 12.60% (35.38 +/- 4.12 flinches/5
min, n=5), 48 +/- 6.75% (24.53 +/- 2.90 flinches/5 min, n=5) and 60 +/- 7.69%
(18.88 +/- 3.58 flinches/5 min, n=5) respectively when compared with the saline
control group (46.80 +/- 2.60 flinches/5 min, n=5). Post-treatment of spantide
i.t. at the highest dose (5 microg) used in the present study 5 min after
bee venom injection also produced a 49% suppression of the flinching reflex
in the control group [post-spantide vs saline: 19.42 +/- 3.15 (n=5) vs 38.42
+/- 3.25 flinches/5 min (n=5)]. Moreover, i.t. pre-treatment with 5 microg
spantide partially prevented the primary and secondary thermal hyperalgesia
from occurring, while it did not show any influence on the development of
primary mechanical hyperalgesia. Neither the established thermal nor mechanical
hyperalgesia identified in the above sites was affected by i.t. post-treatment
with the same dose of spantide 3 h after bee venom injection. Pre and post-treatment
of SR142801 did not produce any significant effect on the bee venom-induced
spontaneous pain and thermal and mechanical hyperalgesia. Our present result
suggests that activation of spinal NK1/2 receptors is involved in both induction
and maintenance of the persistent spontaneous nociception, while it is only
involved in induction of the primary and secondary thermal, but not primary
mechanical hyperalgesia induced by s.c. bee venom injection. The spinal NK3
receptor seems not likely to be involved in the bee venom-induced behavioral
response characterized by spontaneous pain and thermal and mechanical hyperalgesia.
Copyright 2001 Harcourt Publishers Ltd.
PMID: 11346308 [PubMed - indexed for MEDLINE]
| 38: J Vet Med Sci. 2001 Mar;63(3):251-9. |
Bee venom
pretreatment has both an antinociceptive and anti-inflammatory effect on carrageenan-induced
inflammation.
Lee JH, Kwon YB, Han HJ, Mar WC, Lee HJ, Yang IS, Beitz AJ, Kang SK.
Department of Veterinary Physiology,
College of Veterinary Medicine, Seoul National University, Suwon, South Korea.
Although the injection of bee venom (BV) has been reported to evoke tonic
pain and hyperalgesia, there is conflicting evidence in the literature indicating
that BV can also exert an anti-inflammatory and antinociceptive effects on
inflammation. In this regard, BV has been traditionally used in Oriental medicine
to relieve pain and to treat chronic inflammatory diseases such as rheumatoid
arthritis. The present study was designed to test the hypothesis that BV induces
acute nociception under normal conditions, but that it can serve as a potent
anti-inflammatory and antinociceptive agent in a localized inflammatory state.
The experiments were designed to evaluate the effect of BV pretreatment on
carrageenan (CR)-induced acute paw edema and thermal hyperalgesia. In addition,
spinal cord Fos expression induced by peripheral inflammation was quantitatively
analyzed. In normal animals subcutaneous BV injection into the hindlimb was
found to slightly increase Fos expression in the spinal cord without producing
detectable nociceptive behaviors or hyperalgesia. In contrast pretreatment
with BV (0.8 mg/kg) 30 min prior to CR injection suppressed both the paw edema
and thermal hyperalgesia evoked by CR. In addition, there was a positive correlation
between the percent change in paw volume and the expression of Fos positive
neurons in the spinal cord. These results indicate that BV pretreatment has
both antinociceptive and anti-inflammatory effects in CR-induced inflammatory
pain. These data also suggest that BV administration may be useful in the
treatment of the pain and edema associated with chronic inflammatory diseases.
PMID: 11307924 [PubMed - indexed for MEDLINE]
| 39: Pain. 2001 Apr;91(3):367-76. |
Pivotal role
of capsaicin-sensitive primary afferents in development of both heat and mechanical
hyperalgesia induced by intraplantar bee venom injection.
Chen
J, Chen
HS.
Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military
Medical University, 17 West Chang-le Road, Xi'an 710032, People's Republic
of China. patchclp@mail-169.fmmu.edu.cn
To investigate the roles of primary afferent fibers in development of the
bee venom (BV)-induced persistent spontaneous nociception (PSN) and hyperalgesia
(HA), the sciatic nerve or both the sciatic and saphenous nerves of rats were
topically treated with capsaicin respectively under pentobarbital anesthesia
to destroy the capsaicin-sensitive primary afferent (CSPA) fibers. Effect
of the sciatic nerve capsaicin on the formalin-induced PSN was also evaluated.
Destruction of the CSPA fibers of the sciatic nerve or both the sciatic and
saphenous nerves only produced 34 or 69% inhibition of the mean total number
of 1 h BV-induced paw flinches. However, the total number of 1 h formalin-induced
paw flinches was inhibited by 90% (85% for phase 1 and 91% for phase 2). In
naive rats, destruction of the CSPA fibers of the sciatic nerve caused 237
and 60% increase in paw withdrawal thermal latency (PWTL) to radiant heat
in the injection site (paw pad) and at the heel of the treated hind paw compared
to the baseline values. However, it was without significant influence upon
the PWTL in the non-treated side or the paw withdrawal mechanical threshold
(PWMT) to von Frey filament stimuli in both hind paws. In the BV-treated rats,
the CSPA fiber destruction of the sciatic nerve completely blocked development
of the heat and mechanical HA in the BV injection site. However, the reduction
in either PWTL (drop to baseline level) or PWMT (drop by 56% from the baseline
level) at the heel of the BV-treated side was not affected by this treatment.
However, destruction of the CSPA fibers of both the sciatic and saphenous
nerves was able to block development of both heat and mechanical HA in the
whole BV-treated hind paw and heat hyperalgesia in the non-injected hind paw.
Taken together, we conclude that: (1) the CSPA (C- and A delta-) fibers play
a pivotal role in mediation of either the heat or the mechanical hyperalgesia
induced by s.c. BV; (2) the CSPA fibers may play a crucial role in mediation
of the formalin-induced PSN, but play a partial role in the BV-induced nociceptive
process; (3) in addition to the sciatic nerve, the saphenous nerve is also
involved in mediation of the BV-induced PSN as well as heat and mechanical
hyperalgesia, while it is not likely to be involved in the formalin-induced
nociception.
PMID: 11275395 [PubMed - indexed for MEDLINE]
| 40: Pain. 2001 Feb 15;90(3):271-80. |
Bee venom
injection into an acupuncture point reduces arthritis associated edema and
nociceptive responses.
Kwon YB, Lee JD, Lee HJ, Han HJ, Mar WC, Kang SK, Beitz AJ, Lee JH.
Department of Veterinary Physiology,
College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul
National University, Suwon 441-744, South Korea.
Bee venom (BV) has traditionally been used in Oriental medicine to relieve
pain and to treat inflammatory diseases such as rheumatoid arthritis (RA).
While several investigators have evaluated the anti-inflammatory effect of
BV treatment, the anti-nociceptive effect of BV treatment on inflammatory
pain has not been examined. Previous studies in experimental animals suggest
that the therapeutic effect of BV on arthritis is dependent on the site of
administration. Because of this potential site specificity, the present study
was designed to evaluate the anti-nociceptive effect of BV injections into
a specific acupoint (Zusanli) compared to a non-acupoint in an animal model
of chronic arthritis. Subcutaneous BV treatment (1 mg/kg per day) was found
to dramatically inhibit paw edema caused by Freund's adjuvant injection. Furthermore,
BV therapy significantly reduced arthritis-induced nociceptive behaviors (i.e.
the nociceptive scores for mechanical hyperalgesia and thermal hyperalgesia).
These anti-nociceptive/anti-inflammatory effects of BV were observed from
12 days through 21 days post-BV treatment. In addition, BV treatment significantly
suppressed adjuvant-induced Fos expression in the lumbar spinal cord at 3
weeks post-adjuvant injection. Finally, injection of BV into the Zusanli acupoint
resulted in a significantly greater analgesic effect on arthritic pain as
compared to BV injection in to a more distant non-acupoint. The present study
demonstrates that BV injection into the Zusanli acupoint has both anti-inflammatory
and anti-nociceptive effects on Freund's adjuvant-induced arthritis in rats.
These findings raise the possibility that BV acupuncture may be a promising
alternative medicine therapy for the long-term treatment of rheumatoid arthritis.
PMID: 11207399 [PubMed - indexed for MEDLINE]
| 41: Eur J Pain. 2000;4(4):389-401. |
Secondary heat,
but not mechanical, hyperalgesia induced by subcutaneous injection of bee
venom in the conscious rat: effect of systemic MK-
Chen
HS, Chen
J.
Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military
Medical University, Xi'an, 710032, P.R. China.
Subcutaneous (s.c.) administration of bee venom into the plantar surface of
one hind paw in rats has been found to produce an immediate single phase of
persistent spontaneous nociceptive responses (continuously flinching, licking
or lifting the injected paw) for 1-2 h accompanied by a 72-96 hour period
of primary heat and mechanical hyperalgesia in the injection site and a spread
of heat, but not mechanical, hyperalgesia in the non-injected hind paw (Chen
et al., 1999b). To gain insight into the underlying mechanisms of the bee
venom-induced hyperalgesia in particular, we further identified a heat, but
not mechanical, hyperalgesia in an area (paw pad) distant from the injection
site induced by s.c. injection of bee venom into the posterior leg 0.8-
| 42: Neurosci Lett. 2000 May 12;285(2):103-6. |
Involvement
of spinal protein kinase C in induction and maintenance of both persistent
spontaneous flinching reflex and contralateral heat hyperalgesia induced by
subcutaneous bee venom in the conscious rat.
Li KC, Zheng
JH, Chen
J.
Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military
Medical University, 17 West Chang-le Road, Xi'an, China.
To further study the roles of spinal protein kinase C (PKC) in induction and
maintenance of both the persistent spontaneous nociception and the contralateral
heat hyperalgesia induced by subcutaneous (s.c.) bee venom injection, the
effects of intrathecal (i.t.) treatment with a PKC inhibitor, chelerythrine
chloride (CH), were evaluated in conscious rats. Pre-treatment i.t. with CH
at three doses of 0.01, 0.1 and 1 nmol produced a dose-dependent suppressive
effect on the flinching reflex with the inhibitory rates of 39, 48 and 59%,
respectively, when compared with the pre-saline control group. Post-treatment
i.t. with the drug at the highest dose used (1 nmol) also resulted in a 42%
suppression of the flinching reflex compared with the control. Moreover, pre-treatment
i.t. with CH at three doses of 0.01, 0.1 and 1 nmol also produced 12, 22 and
48% inhibition of the contralateral heat hyperalgesia in the pre-saline control
group. Post-treatment i.t. with the drug at the highest dose used (1 nmol)
also resulted in a 35% reversal effect on the established contralateral heat
hyperalgesia. The present result suggests that activation of PKC in the spinal
cord contributes to the induction and maintenance of both peripherally-dependent
persistent spontaneous pain and contralateral heat hyperalgesia which is dependent
upon central sensitization.
PMID: 10793237 [PubMed - indexed for MEDLINE]
| 43: Neurosci Lett. 2000 Apr 21;284(1-2):45-8. |
Contralateral
heat hyperalgesia induced by unilaterally intraplantar bee venom injection
is produced by central changes: a behavioral study in the conscious rat.
Chen
HS, Chen
J, Sun
YY.
Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military
Medical University, 17 West Chang-le Road, Xi'an, China.
In a previous study, we found that subcutaneous (s.c.) intraplantar injection
of bee venom unilaterally could produce bilateral heat hyperalgesia. However,
the bee venom-induced heat hyperalgesia identified in the injection site was
presumed to be different from that identified in the contralateral hindpaw,
since the former co-existed with the mechanical hyperalgesia while the latter
did not. The aim of the present study was to testify whether the contralateral
heat hyperalgesia identified in the bee venom model was a consequence of central
changes. The radiant heat and von Frey-type filaments were applied to both
the injection site and the contralateral pawpad of conscious rats prior to
and 4 h after s.c. bee venom injection. After confirmation of the development
of primary heat and mechanical hyperalgesia and contralateral heat hyperalgesia
following s.c. bee venom, the sciatic nerve of the injection side was transected.
After axotomy, the bee venom-induced heat hyperalgesia in the non-injected
hindpaw was not altered at all compared with that prior to axotomy. Moreover,
intrathecal pre-treatment with either N-methyl-D-aspartate (NMDA) or non-NMDA
receptor antagonist could prevent the development of the contralateral heat
hyperalgesia. The present results suggest that central sensitization contributes
to development of the bee venom-induced contralateral heat hyperalgesia and
activation of both NMDA and non-NMDA receptors in the spinal cord is involved
in the processing.
PMID: 10771158 [PubMed - indexed for MEDLINE]
| 44: Eur J Pain. 1998;2(4):359-376. |
The contribution
of spinal neuronal changes to development of prolonged, tonic nociceptive
responses of the cat induced by subcutaneous bee venom injection.
Chen
J, Luo
C, Li HL.
Department of Anatomy and K. K. Leung Brain Research Centre, The Fourth Military
Medical University, Xi>>an, 710032, China
To elucidate neurophysiological mechanisms of persistent pain induced by tissue
injury, the present study was designed to investigate the effects of s.c.
bee venom injection on responses of the dorsal horn nociceptive neurons and
those of behavior in anesthetized and awake cats, respectively. A parallel
comparative study was also performed to compare the effects of s.c. bee venom
and formalin injections on neuronal responses by using an extracellular single-unit
recording technique. The present results showed that s.c. bee venom injection
into the peripheral cutaneous receptive field resulted in a protracted, tonic
monophase of increase in spike responses of wide-dynamic-range (WDR) neurons
for more than 1 h, while injection of the same volume of vehicle did not have
such an effect. The mean number of spikes during the 60-min period after bee
venom was 6.74+/-2.58 spikes/s (n=10), which showed a significant increase
in firing rate over the background activity (2.23+/-0.96 spikes/s). Behavioral
observations showed that s.c. bee venom injection into the dorsum of a hind
paw also produced a prolonged, tonic single phase of response indicative of
pain, suggesting that central neuronal changes may contribute to development
of bee venom-induced prolonged, tonic pain in cats. The increased neuronal
firing induced by s.c. bee venom could be suppressed by a single dose of i.v.
morphine and resumed by naloxone. Blockade of the sciatic nerve with lidocaine
resulted in a complete suppression of the bee venom-induced neuronal firing,
suggesting that the central neuronal changes following s.c. bee venom are
peripherally-dependent. Comparative studies showed that the duration and frequency
of the bee venom-induced neuronal responses were comparable to those induced
by s.c. formalin; however, responses of WDR neurons to mechanical stimuli
applied to the injection site of the two chemical agents were quite different.
Bee venom produced a significant enhancement of mechanical responses of WDR
neurons, while, on the contrary, formalin produced a desensitization of sensory
receptors in the injection site, suggesting that the two tonic pain models
may have different underlying mechanisms. Copyright 1998 European Federation
of Chapters of the International Association for the Study of Pain.
PMID: 10700331 [PubMed - as supplied by publisher]
| 45: Pain. 2000 Jan;84(1):111-2. |
Comment on:
· Pain. 1996 Aug;66(2-3):271-7.
· Pain. 1998 May;76(1-2):115-25.
The bee venom test:
comparisons with the formalin test with injection of different venoms.
Lariviere WR,
Melzack R.
Publication Types:
· Comment
· Letter
PMID: 10681241 [PubMed - indexed for MEDLINE]
| 46: Neurosci Lett. 2000 Jan 7;278(1-2):41-4. |
Modulatory roles
of the adenosine triphosphate P2x-purinoceptor in generation of the persistent
nociception induced by subcutaneous bee venom injection in the conscious rat.
Zheng
JH, Chen
J.
Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military
Medical University, Xi'an, People's Republic of China.
To study the role of adenosine triphosphate (ATP) P2x-purinoceptor in the
persistent nociceptive response induced by subcutaneous (s.c.) bee venom injection,
we used a selective P2x receptor antagonist, pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic
acid (PPADS), to evaluate whether spinal P2x receptor play a role in development
of spontaneous persistent pain. Injection s.c. of bee venom into the plantar
surface of one hindpaw in the conscious rat produces a monophasic, prolonged
persistent nociception characterized by continuously flinching reflex of the
injected paw for 1-2 h. Intrathecal (i.t.) pretreatment with PPADS at two
lower doses of 5 and 10 microg resulted in suppression of the flinching reflex
in a dose dependent manner with the inhibitory rate 37 and 44%, respectively,
when compared with the control group; whereas i.t. PPADS at a higher dose
of 30 microg failed to produce any inhibitory effect. This result suggests
that activation of P2x-purinoceptor in the spinal cord contributes to the
induction of bee venom-induced prolonged persistent pain. However, the antinociceptive
effect of ATP P2x-purinoceptor antagonist such as PPADS on clinical pathological
pain seems to be limited due to its lack of effectiveness at higher dose.
PMID: 10643796 [PubMed - indexed for MEDLINE]
| 47: Brain Res. 1999 Oct 9;844(1-2):98-105. |
Involvement
of peripheral NMDA and non-NMDA receptors in development of persistent firing
of spinal wide-dynamic-range neurons induced by subcutaneous bee venom injection
in the cat.
Chen
J, Li H, Luo
C, Li Z, Zheng
J.
Department of Anatomy, K.K. Leung Brain Research Centre, The Fourth Military
Medical University, 17 West Chang-le Road, Xi'an, China. patchclp@fmmu.edu.cn
To study the roles of peripheral excitatory amino acids receptor subtypes
N-methyl-D-aspartate (NMDA) and non-NMDA receptors in persistent nociception,
extracellular single unit recording technique was used to assess the effects
of a single dose NMDA and non-NMDA receptor antagonists, AP(5) (5-aminophosphonovaleric
acid) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) or DNQX (6,7-dinitroquinoxaline-2,3-dione),
on s.c. bee venom-induced increase in firing of wide-dynamic-range (WDR) neurons
in the spinal dorsal horn of the urethane-chloralose anesthetized cats. Subcutaneous
bee venom injection into the cutaneous receptive field resulted in a single
phase of increased firing of WDR neurons over the background activity for
more than 1 h. Local pre-administration of AP(5) (200 microg/100 microl) or
CNQX (8.3 microg/100 microl) into the bee venom injection site produced 94%
(1.01+/-0.96 spikes/s, n=5) or 76% (2.97+/-0.58 spikes/s, n=4) suppression
of the increased neuronal firing when compared with local saline (16.32+/-4.55
spikes/s, n=10) or dimethyl sulfoxide (DMSO) (12.37+/-6.36 spikes/s, n=4)
pre-treated group, respectively. Local post-administration of the same dose
of AP(5) produced a similar result to the pre-treatment group with a 67% inhibition
of the mean firing rate, however, the same treatment with CNQX and even a
higher dose of DNQX (100 microg/100 microl) did not produce any inhibition
of the neuronal firing induced by s.c. bee venom injection (DNQX vs. DMSO:
23.91+/-0. 25 vs. 22.14+/-0.04 spikes/s, P=0.0298, n=5). In the control experiments,
local pre-administration of the same dose of AP(5) or CNQX into a region on
the contralateral hindpaw symmetrical to the bee venom injection site produced
no significant influence on the increased firing of the WDR neurons [contralateral
AP(5) vs. saline: 14.17+/-6.27 spikes/s (n=5) vs. 16.32+/-4.55 spikes/s (n=10),
P0.05; contralateral CNQX vs. DMSO: 12.85+/-6.38 spikes/s (n=4) vs. 12. 37+/-6.36
spikes/s (n=4), P0.05], implicating that the suppressive action of local AP(5)
or CNQX was not the result of systemic effects. The present results suggest
that activation of the peripheral NMDA receptors is involved in both induction
and maintenance, while activation of non-NMDA receptors is only involved in
induction, but not in the maintenance of persistent firing of the dorsal horn
WDR neurons induced by s.c. bee venom injection.
PMID: 10536265 [PubMed - indexed for MEDLINE]
| 48: Pain. 1999 Oct;83(1):67-76. |
Primary hyperalgesia
to mechanical and heat stimuli following subcutaneous bee venom injection
into the plantar surface of hindpaw in the conscious rat: a comparative study
with the formalin test.
Chen
J, Luo
C, Li H, Chen
H.
Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military
Medical University, Xi'an, People's Republic of China. deptanat@mail.fmmu.edu.cn
To elucidate the underlying mechanisms of pathological pain, it is important
and necessary to develop an animal model characterized by both spontaneous
tonic pain and hyperalgesia with a prolonged duration post-tissue injury.
In this report, we investigated whether the two animal models of spontaneous
tonic pain (the formalin test and the bee venom test) could develop a hyperalgesia
to mechanical and thermal stimuli in the injured area following subcutaneous
(s.c. ) administration of the two chemical agents into the plantar surface
of one hindpaw in the conscious rats. It was found that the persistent nociceptive
response (flinching and lifting/licking the injected hindpaw) was monophasic
and lasted for 1-2 h followed by a 72-96 h period of reduction in mechanical
threshold and heat latency of withdrawal reflex in the bee venom injection
area; however, in contrast, the spontaneous pain-related response was biphasic
followed by a permanent hypoalgesia or analgesia in the formalin injection
area although the duration and response intensity of spontaneous pain was
comparable with those following bee venom treatment. Subcutaneous. bee venom
injection also produced a distinct reduction of heat latency on the contralateral
hindpaw, while s.c. formalin did not. On the other hand, s.c. bee venom injection
produced a striking edema and redness of the plantar surface for nearly the
same period as the development of hyperalgesia, while the edema and redness
could not be obviously observed after the formalin treatment. In the control
study, repetitive suprathreshold mechanical or heat stimuli applied to the
plantar surface with or without saline treatment did not significantly influence
the mechanical threshold or heat latency, suggesting that the phenomena of
mechanical and heat hyperalgesia were not the effects of vehicle treatment
or those of the stimulus modalities themselves. Taken together, our present
results showed that in contrast to s.c. formalin injection, subcutaneous.
bee venom injection produced little tissue damage but a striking inflammation
accompanied by a prolonged spontaneous pain and a pronounced primary hyperalgesia
to mechanical and heat stimuli in the treated hindpaw and a heat, but not
mechanical, hyperalgesia in the contralateral hindpaw, implicating that bee
venom model may have more advantages over the formalin test and probably other
chemoirritants to study the neural mechanisms underlying pathological pain
and, especially, the relationship between spontaneous pain and development
of hyperalgesia.
PMID: 10506673 [PubMed - indexed for MEDLINE]
| 49: Brain Res. 1998 Sep 28;806(2):175-85. |
Spatial and
temporal expression of c-Fos protein in the spinal cord of anesthetized rat
induced by subcutaneous bee venom injection.
Luo
C, Chen
J, Li HL, Li JS.
Department of Anatomy and K.K. Leung Brain Research Centre, The Fourth Military
Medical University, Xi'an 710032, China.
In order to study central neuronal components involved in subcutaneous (s.c.)
bee venom-induced persistent pain (a new tonic pain model), we use Fos immunostaining
technique to study the spatial and temporal patterns of neuronal activity
in the spinal cord of anesthetized rats. Following intraplantar bee venom
injection, Fos-like immunoreactive (ir) neurons were only seen from L1 to
S3 rostrocaudally with distinct distribution at L4-5 segments. At segments
of L1-2 and S1-3, Fos-ir labelings were diffusely and symmetrically distributed
on both sides of the gray matter; however, at L4-5 segments, Fos-ir neurons
were densely localized in medial portion of laminae I-II, less densely in
laminae V-VI and a few in laminae VII and X ipsilateral to the injection side.
No Fos labeling was seen in ventral horn of the spinal cord at L4-5 segments.
Fos protein began to express only within lamina I at 0.5 h, but increased
over the whole dorsal horn at 1 h and reached peak labeling at 2 h after bee
venom. Expression of c-Fos in laminae I-II decreased at 4 h, and completely
disappeared at 24 h, however, labeling in laminae V-VI disappeared much slowly
and existed even at 96 h after bee venom. Within laminae III-IV, Fos-ir neurons
could not be seen at 0.5 h, but began to be seen at 1 h and appeared to exist
even at 24 h after bee venom. Systemic morphine suppressed c-Fos expression
dose-dependently in both superficial and deep layers of dorsal horn and the
latter region was much more sensitive to morphine than the former one. The
present results demonstrated that prolonged neuronal activities in superficial
and deep layers of dorsal horn were essential to mediation of bee venom induced
tonic pain and may have different roles in generation and/or modulation of
spontaneous pain and hyperalgesia and allodynia. Copyright 1998 Elsevier Science
B.V.
PMID: 9739136 [PubMed - indexed for MEDLINE]
| 50: Pain. 1996 Aug;66(2-3):271-7. |
Comment in:
The bee venom test:
a new tonic-pain test.
Lariviere
WR, Melzack
R.
Department of Psychology, McGill University, Montreal, Quebec, Canada.
The present study describes a new test of tonic pain to be used as an animal
model of persistent pain. First, pain responses and edema produced by subcutaneous
injection of increasing doses of honey bee venom into the hind paw of the
rat were quantified. Second, the effect of morphine and aspirin on the pain
responses was investigated. Finally, the response to concurrent injections
of bee venom and formalin was examined. Subcutaneous injection of bee venom
produced local inflammation, tonic-pain responses lasting from 10 min to more
than 1 h, and marked edema lasting from 3 h to more than 48 h. Increasing
doses of bee venom produced higher mean pain scores and increased durations
of responding. The time course of the edema did not follow the time course
of the pain responses. Analgesia was produced by morphine and aspirin, indicating
that the bee venom test can be used to test analgesic drugs. Concurrent administration of bee venom and formalin produced
pain responses similar to formalin alone, with a less profound interphase
depression and a longer duration. The data suggest that the bee venom test
is a valid animal model of experimental tonic pain.
PMID: 8880850 [PubMed - indexed for MEDLINE]
| 51: Zhongguo Zhong Xi Yi Jie He Za Zhi. 1993 Apr;13(4):226-7, 198. |
[Comparison of anti-inflammatory,
analgesic activities, anaphylactogenicity and acute toxicity between bee venom
and its peptides]
[Article in Chinese]
Chen CY, Chen WX, Sun X.
Nanjing Institute of Biochemical Pharmacy.
Bee venom 1.0-2.0 mg/kg and bee venom peptides 1.0-2.0 mg/kg inhibited several
inflammatory processes, such as ear swelling induced by xylene in mice, edema
produced by injecting 1% carrageenin 0.1 ml beneath the plantar surface of
hind paw in rats and showed a marked analgesic action induced by the hot plate
and potassium antimony tartrate. Bee venom peptides had a markedly more effective
action as compared with bee venom itself. The anaphylactogenicity of bee venom
peptides was apparently milder than that of bee venom. The LD50 of bee venom
ip in mice and bee venom peptides was 7.4 mg/kg and 7.9 mg/kg respectively.
PMID: 8400773 [PubMed - indexed for MEDLINE]
| 52: Recent Adv Stud Cardiac Struct Metab. 1975;10:401-10. |
An enzyme mechanism in explanation
of pain in angina pectoris.
Oster KA, Ross DJ.
The effect of catecholamines, represented by epinephrine and norepinephrine,
on the activity of phospholipase A2 from bee venom was studied. It was shown
that the hydrolysis of l-alpha-lecithin to lysolecithin and a fatty acid was
considerably activated by preincubation of the lecithin with the biogenic
amine. On the other hand, addition of nitroglycerin or propranolol to the
enzyme solution considerably curtailed activation by the catecholamines. The
pharmacological effect of the split products of l-alpha-lecithin, free fatty
acids (FFA), and lysolecithin in the nascent state on the myocardial cell
membrane might be more plausible than the commonly accepted theory that the
FFA derive from lipolysis of remote fat deposits. Certain arrhythmias and
ion imbalances might be caused by catecholamine activation of phospholipase
A2. Of great pharmacological interest is the observation that this activation
is inhibited by a beta-adrenergic blocking agent without the presence of cyclic
adenosine monophosphate as a messenger. The reaction may serve as a model
for the study of the pharmacological influence of nitroglycerin and propranolol
on angina pectoris.
PMID: 813283 [PubMed - indexed for MEDLINE]
| 53: Vrach Delo. 1965 May;5:148. |
[Experience with iontophoresis
of bee venom in lumbar sciatica]
[Article in Russian]
Prikhod'ko VI.
PMID: 5854483 [PubMed - indexed for MEDLINE]
| 54: Klin Med (Mosk). 1959 May;37(5):141-2. |
[Use of bee venom in sciatica
and radiculitis.]
[Article in Russian]
SOKOLOV IM.
PMID: 13665942 [PubMed - OLDMEDLINE for Pre1966]
| 55: Klin Med (Mosk). 1959 May;37(5):139-41. |
[Influence of bee venom on the
pain syndrome.]
[Article in Russian]
VLADIMIROVA KF.
PMID: 13665941 [PubMed - OLDMEDLINE for Pre1966]