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.
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. firstname.lastname@example.org
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. email@example.com
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. firstname.lastname@example.org
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. email@example.com
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. firstname.lastname@example.org
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.
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.
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. email@example.com
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.
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. firstname.lastname@example.org
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. email@example.com
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.
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]
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]
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]
PMID: 13665941 [PubMed - OLDMEDLINE for Pre1966]