Melittin-induced Nociceptive Responses are Alleviated by Cyclooxygenase-1 Inhibitor

  • Kim, Joo-Hyun (Department of Physiology, College of Medicine, Hanyang University) ;
  • Shin, Hong-Kee (Department of Physiology, College of Medicine, Hanyang University) ;
  • Lee, Kyung-Hee (Department of Physiology, College of Medicine, Hanyang University)
  • Published : 2006.02.21

Abstract

Melittin-induced pain model has been known to be very useful for the study of pain mechanism. Melittin-induced nociceptive responses are reported to be modulated by the changes in the activity of excitatory amino acid receptor, calcium channel, spinal serotonin receptor and extracellular signaling-regulated kinase. The present study was undertaken to investigate the role of cyclooxygenase (COX) in the melittin-induced nociception. Changes in mechanical threshold, flinchings and paw thickness were measured before and after intraplantar injection of melittin in the rat hind paw. Also studied were the effects of intraperitonealy administered diclofenac (25 mg & 50 mg/kg), piroxicam (10 mg & 20 mg/kg) and meloxicam (10 mg & 20 mg/kg) on the melittin-induced nociceptions. Intraplantar injection of melittin caused marked reduction of mechanical threshold that was dose-dependently attenuated by non-selective COX inhibitor (diclofenac) and selective COX-1 inhibitor (piroxicam), but not by COX-2 inhibitor (meloxicam). Melittin-induced flinchings were strongly suppressed by non-selective COX and COX-1 inhibitor, but not by COX-2 inhibitor. None of the COX inhibitors had inhibitory effects on melittin-induced increase of paw thickness (edema). These experimental findings suggest that COX-1 plays an important role in the melittin-induced nociceptive responses.

Keywords

References

  1. Ballou LR, Botting RM, Goorha S, Zhang J, Vane JR. Nociception in cyclooxygenase isozyme-deficient mice. Proc Natl Acad Sci USA 97: 10272-10276, 2000
  2. Beiche F, Klein T, Nüsing R, Neuhuber W, Goppelt-Struebe M. Localization of cyclooxygenase-2 and prostaglandin E2 receptor EP3 in the rat lumbar spinal cord. J Neuroimmunol 89: 26-34, 1998 https://doi.org/10.1016/S0165-5728(98)00061-7
  3. Bomalaski JS, Ford T, Hudson AP, Clark MA. Phospholipase A2-activating protein induces the synthesis of IL-1 and TNF in human monocytes. J Immunol 154: 4027-4031, 1995
  4. Burch RM, Connor JR, Axelrod J. Interleukin 1 amplifies receptormediated activation of phospholipase A2 in 3T3 fibroblasts. Proc Natl Acad Sci USA 85: 6306-6309, 1988
  5. Chen HS, Chen J. Secondary heat, but not mechanical, hyperalgesia induced by subcutaneous injection of bee venom in the conscious rat: effect of systemic MK-801, a non-competitive NMDA receptor antagonist. Eur J Pain 4: 389-401, 2000 https://doi.org/10.1053/eujp.2000.0197
  6. Chen HS, Chen J, Sun YY. Contralateral heat hyperalgesia induced by unilaterally intraplantar bee venom injection is produced by central changes: a behavioral study in the conscious rat. Neurosci Lett 284: 45-48, 2000 https://doi.org/10.1016/S0304-3940(00)00955-1
  7. Chen HS, Li MM, Shi J, Chen J. Supraspinal contribution to development of both tonic nociception and referred mirror hyperalgesia. Anesthesiology 98: 1231-1236, 2003 https://doi.org/10.1097/00000542-200305000-00027
  8. Chen J, Chen HJ. Pivotal role of capsaicin-sensitive primary afferents in development of both heat and mechanical hyperalgesia induced by intraplantar bee venom injection. Pain 91: 367-376, 2001 https://doi.org/10.1016/S0304-3959(00)00458-9
  9. Chen J, Li H, Luo C, Li Z, Zheng J. 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. Brain Res 844: 98-105, 1999a https://doi.org/10.1016/S0006-8993(99)01841-7
  10. Chen J, Luo C, Li HL. The contribution of spinal neuronal changes to development of prolonged, tonic nociceptive responses of the cat induced by subcutaneous bee venom injection. Eur J Pain 2: 359-376, 1998 https://doi.org/10.1016/S1090-3801(98)90034-9
  11. Chen J, Luo C, Li H, Chen H. 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. Pain 83: 67-76, 1999b https://doi.org/10.1016/S0304-3959(99)00075-5
  12. Choi OH, Padgett WL, Daly JW. Effects of the amphiphilic peptides melittin and mastoparan on calcium influx, phosphoinositide breakdown and arachidonic acid release in rat pheochromocytoma PC12 cells. J Pharmacol Exp Ther 260: 369-375, 1992
  13. Chopra B, Giblett S, Little JG, Donaldson LF, Tate S, Evans RJ, Grubb BD. Cyclooxygenase-1 is a marker for a subpopulation of putative nociceptive neurons in rat dorsal root ganglion. Eur J Neurosci 12: 911-920, 2000 https://doi.org/10.1046/j.1460-9568.2000.00979.x
  14. Engelhardt G, Bögel R, Schnitzler C, Utzmann R. Meloxicam: influence on arachidonic acid metabolism. Biochem Pharmacol 51: 29-38, 1996 https://doi.org/10.1016/0006-2952(95)02110-8
  15. Euchenhofer C, Maihofner C, Brune K, Tegeder I, Geisslinger G. Differential effect of selective cyclooxygenase-2 (COX-2) inhibitor NS 398 and diclofenac on formalin-induced nociception in the rat. Neurosci Lett 248: 25-28, 1998 https://doi.org/10.1016/S0304-3940(98)00325-5
  16. Gilroy DW, Tomlinson A, Willoughby DA. Differential effects of inhibition of isoforms of cyclooxygenase (COX-1, COX-2) in chronic inflammation. Inflamm Res 47: 79-85, 1998 https://doi.org/10.1007/s000110050285
  17. Hay CH, Trevethick MA, Wheeldon A, Bowers JS, de Belleroche JS. The potential role of spinal cord cyclooxygenase-2 in the development of Freund's complete adjuvant-induced changes in hyperalgesia and allodynia. Neuroscience 78: 843-850, 1997 https://doi.org/10.1016/S0306-4522(96)00598-2
  18. Inoue A, Ikoma K, Morioka N, Kumagai K, Hashimoto T, Hide I, Nakata Y. $Interleukin-1\beta$ induces substance P release from primary afferent neurons through the cyclooxygenase-2 system. J Neurochem 73: 2206-2213, 1999 https://doi.org/10.1046/j.1471-4159.1999.02206.x
  19. Kawamura T, Yamauchi T, Koyama M, Maruyama T, Akira T, Nakamura N. Expression of prostaglandin EP2 receptor mRNA in the rat spinal cord. Life Sci 61: 2111-2116, 1997 https://doi.org/10.1016/S0024-3205(97)00884-9
  20. Kim HW, Kwon YB, Ham TW, Roh DH, Yoon SY, Lee HJ, Han HJ, Yang IS, Beitz AJ, Lee JH. Acupoint stimulation using bee venom attenuates formalin-induced pain behavior and spinal cord Fos expression in rats. J Vet Med Sci 65: 349-355, 2003 https://doi.org/10.1292/jvms.65.349
  21. Kim HW, Kwon YB, Han HJ, Yang IS, Beitz AJ, Lee JH. Antinociceptive mechanisms associated with diluted bee venom acupuncture (apipuncture) in the rat formalin test: involvement of descending adrenergic and serotonergic pathways. Pharmacol Res 51: 183-188, 2005 https://doi.org/10.1016/j.phrs.2004.07.011
  22. Kim JH, Shin HK. N-methyl-D-aspartate (NMDA) and non-NMDA receptors are involved in the production and maintenance of nociceptive responses by intraplantar injection of bee venom and melittin in the rat. Kor J Physiol Pharmacol 9: 179-186, 2005
  23. Kwon YB, Kim JH, Yoon JH, Lee JD, Han HJ, Mar WC, Beitz AJ, Lee JH. The analgesic efficacy of bee venom acupuncture for knee osteoarthritis: a comparative study with needle acupuncture. Am J Chin Med 29: 187-199, 2001a https://doi.org/10.1142/S0192415X01000228
  24. Kwon YB, Lee JD, Lee HJ, Han HJ, Mar WC, Kang SK, Beitz AJ, Lee JH. Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses. Pain 90: 271-280, 2001b https://doi.org/10.1016/S0304-3959(00)00412-7
  25. Kwon YB, Lee HJ, Han HJ, Mar WC, Kang SK, Yoon OB, Beitz AJ, Lee JH. The water-soluble fraction of bee venom produces antinociceptive and anti-inflammatory effects on rheumatoid arthritis in rats. Life Sci 71: 191-204, 2002 https://doi.org/10.1016/S0024-3205(02)01617-X
  26. Kwon YB, Han HJ, Beitz AJ, Lee JH. Bee venom acupoint stimulation increases Fos expression in catecholaminergic neurons in the rat brain. Mol Cells 17: 329-333, 2004
  27. Kwon YB, Ham TW, Kim HW, Roh DH, Yoon SY, Han HJ, Yang IS, Kim KW, Beitz AJ, Lee JH. Water soluble fraction (<10 kDa) from bee venom reduces visceral pain behavior through spinal $\alpha2$-adrenergic activity in mice. Pharmacol Biochem Behav 80: 181-187, 2005 https://doi.org/10.1016/j.pbb.2004.10.017
  28. Laird JMA, Herrero JF, de la Rubia PG, Cervero F. Analgesic activity of the novel COX-2 preferring NSAID, meloxicam in mono-arthritic rats: Central and peripheral components. Inflamm Res 46: 203-210, 1997 https://doi.org/10.1007/s000110050174
  29. Lariviere WR, Melzack R. The bee venom test: a new tonic-pain test. Pain 66: 271-277, 1996 https://doi.org/10.1016/0304-3959(96)03075-8
  30. Lashbrook JM, Ossipov MH, Hunter JC, Raffa RB, Tallarida RJ, Porreca F. Synergistic antiallodynic effects of spinal morphine with ketorolac and selective COX1- and COX2-inhibitors in nerve-injured rats. Pain 82: 65-72, 1999 https://doi.org/10.1016/S0304-3959(99)00031-7
  31. Lee KH, Kim JS, Kim JH, Shin HK. Spinal serotonin receptors are involved in the modulation of the melittin-induced nociception in the rats. Kor J Physiol Pharmacol 9(Suppl I): S163, 2005
  32. Lee KH, Shin HK, Kim JS, Kim JH. Effect of intrathecal and intraplantar injection of calcium channel antagonsts on melittininduced mechanical hyperalgesia in rats. Kor J Physiol Pharmacol 8(Suppl I): S133, 2004
  33. Li KC, Chen J. Differential roles of spinal protein kinase C and A in development of primary heat and mechanical hypersensitivity induced by subcutaneous bee venom chemical injury in the rat. Neurosignals 12: 292-301, 2003 https://doi.org/10.1159/000075311
  34. Li KC, Chen J. Altered pain-related behaviors and spinal neuronal responses produced by s.c. injection of melittin in rats. Neuroscience 126: 753-762, 2004 https://doi.org/10.1016/j.neuroscience.2004.03.050
  35. Li KC, Zheng JH, Chen J. 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. Neurosci Lett 285: 103-106, 2000 https://doi.org/10.1016/S0304-3940(00)01039-9
  36. Luo C, Chen J, Li HL, Li JS. Spatial and temporal expression of c-Fos protein in the spinal cord of anesthetized rat induced by subcutaneous bee venom injection. Brain Res 806: 175-185, 1998 https://doi.org/10.1016/S0006-8993(98)00721-5
  37. Luttinger D. Determination of antinociceptive efficacy of drugs in mice using different water temperatures in a tail-immersion test. J Pharmacol Meth 13: 351-357, 1985 https://doi.org/10.1016/0160-5402(85)90017-8
  38. Ma W, Du W, Eisenach JC. Role for both spinal cord COX-1 and COX-2 in maintenance of mechanical hypersensitivity following peripheral nerve injury. Brain Res 937: 94-99, 2002 https://doi.org/10.1016/S0006-8993(02)02593-3
  39. Maihofner C, Tegeder I, Euchenhofer C, Dewitt D, Brune K, Bang R, Neuhuber W, Geisslinger G. Localization and regulation of cyclooxygenase-1 and -2 and neuronal nitric oxide synthase in mouse spinal cord. Neuroscience 101: 1093-1108, 2000 https://doi.org/10.1016/S0306-4522(00)00361-4
  40. Masferrer JL, Zweifel BS, Manning PT, Hauser SD, Leahy KM, Smith WG, Isakson PC, Seibert K. Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic. Proc Natl Acad Sci USA 91: 3228-3232, 1994
  41. Motta, AF, Gomes BJN, da Fonseca PJC, Tonussi CR. The antinociceptive effect of iontophoretic direct application of diclofenac to arthritic knee-joints of rats. Life Sci 73: 1995-2004, 2003 https://doi.org/10.1016/S0024-3205(03)00539-3
  42. O'Banion M, Miller JC, Chang JW, Kaplan MD, Coleman PD. Interleukin- $1\beta$ induces prostaglandin G/H synthase-2 (cyclooxygenase- 2) in primary murine astrocyte cultures. J Neurochem 66: 2532- 2540, 1996 https://doi.org/10.1046/j.1471-4159.1996.66062532.x
  43. Ochi T, Goto T. Differential effect of FR122047, a selective cyclooxygenase- 1 inhibitor, in rat chronic models of arthritis. Br J Pharmacol 135: 782-788, 2002 https://doi.org/10.1038/sj.bjp.0704511
  44. Omana-Zapata I, Bley KR. A stable prostacyclin analog enhances ectopic activity in rat sensory neurons following neuropathic injury. Brain Res 904: 85-92, 2001 https://doi.org/10.1016/S0006-8993(01)02486-6
  45. Roh DH, Kim HW, Yoon SY, Kang SY, Kwon YB, Han HJ, Beitz AJ, Lee JH. Diluted bee venom suppresses formalin-induced pain behavior and induces spinal Fos expression via capsaicininsensitive afferents. Kor J Physiol Pharmacol 8(Suppl I): S125, 2004a
  46. Roh DH, Kwon YB, Kim HW, Ham TW, Yoon SY, Kang SY, Han HJ, Lee HJ, Beitz AJ, Lee JH. Acupoint stimulation with diluted bee venom (apipuncture) alleviates thermal hyperalgesia in a rodent neuropathic pain model: involvement of spinal alpha2- adrenoceptors. J Pain 5: 297-303, 2004b https://doi.org/10.1016/j.jpain.2004.05.003
  47. Safieh-Garabedian B, Dardenne M, Kanaan SA, Atweh SF, Jabbur SJ, Saade NE. The role of cytokines and prostaglandin-E2 in thymulin induced hyperalgesia. Neuropharmacology 39: 1653- 1661, 2000 https://doi.org/10.1016/S0028-3908(99)00247-6
  48. Shier WT. Activation of high levels of endogenous phospholipase A2 in cultured cells. Proc Natl Acad Sci USA 76: 195-199, 1979
  49. Shin HK, Kim JH. Melittin selectively activates capsaicin-sensitive primary afferent fibers. Neuroreport 15: 1745-1749, 2004 https://doi.org/10.1097/01.wnr.0000135919.37807.a7
  50. Shin HK, Lee KH, Lee SE. Comperative study on the nociceptive responses induced by whole bee venom and melittin. Kor J Physiol Pharmacol 8: 281-288, 2004a
  51. Shin HK, Lee KH, Kim JS, Lee SE, Jun JH. Intracellular calcium ions play an inportant role in the melittin-induced nociceptive responses in the rat. Kor J Physiol Pharmacol 8(Suppl I): S124, 2004b
  52. Southall MD, Michael RL, Vasko MR. Intrathecal NSAIDs attenuate inflammation-induced neuropeptide release from rat spinal cord slices. Pain 78: 39-48, 1998 https://doi.org/10.1016/S0304-3959(98)00113-4
  53. Yaksh TL, Dirig DM, Conway CM, Svensson C, Luo ZD, Isakson PC. The acute antihyperalgesic action of nonsteroidal, antiinflammatory drugs and release of spinal prostaglandin E2 is mediated by the inhibition of constitutive spinal cyclooxygenase- 2 (COX-2) but not COX-1. J Neurosci 21: 5847-5853, 2001 https://doi.org/10.1523/JNEUROSCI.21-16-05847.2001
  54. Yamamoto T, Sakashita Y. COX-2 inhibitor prevents the development of hyperalgesia induced by intrathecal NMDA or AMPA. Neuroreport 9: 3869-3873, 1998 https://doi.org/10.1097/00001756-199812010-00019
  55. You HJ, Chen J, Morch CD, Arendt-Nielsen L. Differential effect of peripheral glutamate (NMDA, non-NMDA) receptor antagonists on bee venom-induced spontaneous nociception and sensitization. Brain Res Bull 58: 561-567, 2002 https://doi.org/10.1016/S0361-9230(02)00806-7
  56. Yu YQ, Chen J. Activation of spinal extracellular signalingregulated kinases by intraplantar melittin injection. Neurosci Lett 381: 194-198, 2005 https://doi.org/10.1016/j.neulet.2005.02.033
  57. Yue HY, Fujita T, Koga A, Liu T, Kawasaki Y, Nakatsuka T, Kumamoto E. Effect of melittin on glutamatergic transmission in rat substantia gelatinosa neurons. Soc Neurosci Abstr Program NO. 982.10, 2005
  58. Zhang Y, Shaffer A, Portanova J, Seibert K, Isakson PC. Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 production. J Pharmacol Exp Ther 283: 1069-1075, 1997
  59. Zhao Z, Chen SR, Eisenach JC, Busija DW, Pan HL. Spinal cyclooxygenase-2 is involved in development of allodynia after nerve injury in rats. Neuroscience 97: 743-748, 2000 https://doi.org/10.1016/S0306-4522(00)00052-X
  60. Zheng JH, Chen J. Modulatory roles of the adenosine triphosphate P2x-purinoceptor in generation of the persistent nociception induced by subcutaneous bee venom injection in the conscious rat. Neurosci Lett 278: 41-44, 2000 https://doi.org/10.1016/S0304-3940(99)00896-4
  61. Zheng JH, Chen J. 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. Neuropeptides 35: 32-44, 2001 https://doi.org/10.1054/npep.2000.0841
  62. Zhu X, Conklin D, Eisenach JC. Cyclooxygenase-1 in the spinal cord plays an important role in postoperative pain. Pain 104: 15-23, 2003 https://doi.org/10.1016/S0304-3959(02)00465-7