The Korean Journal of Pain

  • 제18권1호
  • /
  • Pages.1-9
  • /
  • 2005
  • /
  • 2005-9159(pISSN)
  • /
  • 2093-0569(eISSN)
대한통증학회 (The Korean Pain Society)
권호 표지

Antinociceptive Effects of Intrathecal Metabotropic Glutamate Receptor Compounds and Morphine in Rats

  • Choi, Jeong II (Department of Anesthesiology and Pain Medicine, Medical School, Chonnam National University) ;
  • Lee, Hyung Kon (Department of Anesthesiology and Pain Medicine, Medical School, Chonnam National University) ;
  • Chung, Sung Tae (Department of Anesthesiology and Pain Medicine, Medical School, Chonnam National University) ;
  • Kim, Chang Mo (Department of Anesthesiology and Pain Medicine, Medical School, Chonnam National University) ;
  • Bae, Hong Beom (Department of Anesthesiology and Pain Medicine, Medical School, Chonnam National University) ;
  • Kim, Seok Jai (Department of Anesthesiology and Pain Medicine, Medical School, Chonnam National University) ;
  • Yoon, Myung Ha (Department of Anesthesiology and Pain Medicine, Medical School, Chonnam National University) ;
  • Chung, Sung Su (College of Dentistry, Medical School, Chonnam National University) ;
  • Jeong, Chang Young (Department of Anesthesiology and Pain Medicine, Medical School, Chonnam National University)
  • 투고 : 2005.04.19
  • 심사 : 2005.05.20
  • 발행 : 2005.06.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Background: Spinal metabotropic glutamate receptors (mGluRs) and opioid receptors are involved in the modulation of nociception. Although opioid receptors agonists are active for pain, the effects of the compounds for the mGluRs have not been definitely investigated at the spinal level. We examined the effects of the intrathecal mGluR compounds and morphine in the nociceptive test, and then we further clarified the role of the spinal mGluRs. In addition, the nature of the pharmacological interaction after the coadministration of mGluRs compounds with morphine was determined. Methods: Catheters were inserted into the intrathecal space of male SD rats. For the induction of pain, $50{\mu}l$ of 5% formalin solution or a thermal stimulus was applied to the hindpaw. An isobolographic analysis was used for the evaluation of the drug interaction. Results: Neither group I mGluR compounds nor group III mGluR compounds produced any antinociceptive effect in the formalin test. The group II mGluR agonist (APDC) had little effect on the formalin-induced nociception. The group II mGluR antagonist (LY 341495) caused a dose-dependent suppression of the phase 2 flinching response on the formalin test, but it did not reduce the phase 1 response of the formalin test nor did it increase the withdrawal latency of the thermal stimulus. Isobolographic analysis revealed a synergistic interaction after the intrathecal delivery of a LY 341495-morphine mixture. Conclusions: These results suggest that group II mGluRs are involved in the facilitated processing at the spinal level, and the combination of LY 341495 with morphine may be useful to manage the facilitated pain state.

키워드

참고문헌

  1. Veda M, Kuraishi Y, Sugimoto K, Satoh M: Evidence that glutamate is released from capsaicin-sensitive primary afferent fibers in rats: study with on-line continuous monitoring of glutamate. Neurosci Res 1994; 20: 231-7. https://doi.org/10.1016/0168-0102(94)90092-2
  2. Dickenson AH, Chapman V, Green GM: The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord. Gen Pharmacol 1997; 28: 633-8. https://doi.org/10.1016/S0306-3623(96)00359-X
  3. Baranauskas G, Nistri A: Sensitization of pain pathways in the spinal cord: cellular mechanisms. Prog Neurobiol 1998; 54: 349-65. https://doi.org/10.1016/S0301-0082(97)00067-1
  4. Conn PJ, Pin JP: Pharmacology and functions of meraborropic glutamate receptors. Annu Rev Pharmacol Toxicol 1997; 37: 205-37. https://doi.org/10.1146/annurev.pharmtox.37.1.205
  5. Yashpal K, Fisher K, Chabot JG, Coderre TJ: Differential effects of NMDA and group I mGluR antagonists on both nociception and spinal cord protein kinase C translocation in the formalin test and a model of neuropathic pain in rats. Pain 2001; 94: 17-29. https://doi.org/10.1016/S0304-3959(01)00337-2
  6. Karim F, Wang CC, Gereau RW 4th: Metabotropic glutamate receptor subtypes I and 5 are activators of extracellular signalregulated kinase signaling required for inflammatory pain in mice. J Neurosci 200 I; 21: 3771-9.
  7. Fisher K, Coderre TJ: The contribution of metabotropic glutamate receptors (mGluRs) to formalin-induced nociception. Pain 1996; 68: 255-63. https://doi.org/10.1016/S0304-3959(96)03212-5
  8. Dolan S, Nolan AM: Behavioral evidence supporting a differential role for spinal gtoup I and II metabotropic gluramare receptors in inflammatory hyperalgesia in sheep. Neuropharmacology 2002; 43: 319-26. https://doi.org/10.1016/S0028-3908(02)00107-7
  9. Walker K, Bowes M, Panesar M, Davis A, Gentry C, Kesingland A, et al: Metabotropic glutamate receptor subtype 5 (mGlu5) and nociceptive function. I. Selective blockade of mGlu5 receptors in models of acute, persistent and chronic pain. Neuropharmacology 2001; 40: 1-9. https://doi.org/10.1016/S0028-3908(00)00113-1
  10. Walker K, Reeve A, Bowes M, Winter J, Wotherspoon G, Davis A, et al: mGlu5 receptors and nociceptive function II. mGlu5 receptors functionally expressed on peripheral sensory neurones mediate inflammatory hyperalgesia. Neuropharmacology 2001; 40: 10-9. https://doi.org/10.1016/S0028-3908(00)00114-3
  11. Simmons RM, Webster AA, Kalra AB, Iyengar S: GtoUP II mGluR receptor agonisrs are effective in persistent and neuropathic pain models in rats. Pharmacol Biochem Behav 2002; 73: 419-27. https://doi.org/10.1016/S0091-3057(02)00849-3
  12. Neugebauer V, Chen PS, Willis WD: Groups II and III merabotropic glutamate receptors differentially modulate brief and prolonged nociception in primate STT cells. J Neurophysiol 2000; 84: 2998-3009. https://doi.org/10.1152/jn.2000.84.6.2998
  13. Gerber G, Zhong J, Youn D, Randic M: Group II and group III rnetaborropic glutamate receptor agonists depress synaptic transmission in the rat spinal cord dorsal horn. Neuroscience 2000;100: 393-406. https://doi.org/10.1016/S0306-4522(00)00269-4
  14. Thomas NK, Wright RA, Howson PA, Kingston AE, Schoepp DD, Jane DE: (S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic gluramate receptors on primary afferent terminals in the neonatal rat spinal cord. Neuropharmacology 2001; 40: 311-8. https://doi.org/10.1016/S0028-3908(00)00169-6
  15. Przesmycki K, Dzieciuch JA, Czuczwar SJ, Kleinrok Z: Isobolographic analysis of interaction between intrathecal morphine and clonidine in the formalin test in rats. Eur J Pharmacol 1997; 337: 11-7. https://doi.org/10.1016/S0014-2999(97)01280-6
  16. Nemirovsky A, Chen L, Zelman V, Jurna 1: The antinociceptive effect of the combination of spinal morphine with systemic morphine or buprenorphine, Anesth Analg 2001; 93: 197-203.
  17. Yaksh TL, Rudy TA: Chronic catheterization of the spinal subarachnoid space. Physiol Behav 1976; 17: 1031-6. https://doi.org/10.1016/0031-9384(76)90029-9
  18. Hargreaves K, Dubner R, Brown F, Flores C, Joris J: A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988; 32: 77-88. https://doi.org/10.1016/0304-3959(88)90026-7
  19. Dirig DM, Salami A, Rathbun ML, Ozaki GT, Yaksh TL: Characterization of variables defining hindpaw withdrawal latency evoked by radiant thermal stimuli. J Neurosci Methods 1997; 76: 183-91. https://doi.org/10.1016/S0165-0270(97)00097-6
  20. Yoon MH, Choi J1: Pharmacologic interaction between cannabinoid and either clonidine or neostigmine in the rat formalin test. Anesthesiology 2003; 99: 701-7. https://doi.org/10.1097/00000542-200309000-00027
  21. Tallarida RJ, Murray RB: Manual of pharmacologic calculations with computer programs. 2nd ed. New York, Springer-Verlag. 1987, pp 1-95.
  22. Ohishi H, Shigemoto R, Nakanishi S, Mizuno N: Distribution of the mRNA for a meraborropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study. J Comp Neurol 1993; 335: 252-66. https://doi.org/10.1002/cne.903350209
  23. Valerio A, Paterlini M, Boifava M, Memo M, Spano P: Metabotropic glutamate receptor mRNA expression in rat spinal cord. Neuroreporr 1997; 8: 2695-9. https://doi.org/10.1097/00001756-199708180-00012
  24. Vidnyanszky Z, Hamori J, Negyessy L, Ruegg D, Knopfel T, Kuhn R, er al: Cellular and subcellular localization of the mGluR5a meraborropic glutamate receptor in rat spinal cord. Neuroreport 1994; 6: 209-13. https://doi.org/10.1097/00001756-199412300-00053
  25. Jia H, Rusrioni A, Valtschanoff JG: Metabotropic glutamate receptors in superficial laminae of the rat dorsal horn. J Comp Neurol 1999; 410: 627-42. https://doi.org/10.1002/(SICI)1096-9861(19990809)410:4<627::AID-CNE9>3.0.CO;2-8
  26. Tang FR, Sim MK: Pre- and/or post-synaptic localisation of metabotropic glutamate receptor Ialpha (mGluRlalpha) and 2/3 (mGluR2/3) in the rat spinal cord. Neurosci Res 1999; 34: 73-8. https://doi.org/10.1016/S0168-0102(99)00035-8
  27. Azkue J], Marcos JM, Elezgarai I, Benitez R, Osorio A, Diez J, et al: The meraborropic glutamate receptor subtype mGluR 2/3 is located at extrasynaptic loci in rat spinal dorsal horn synapses. Neurosci Lett 2000; 287: 236-8. https://doi.org/10.1016/S0304-3940(00)01189-7
  28. Li H, Ohishi H, Kinoshita A, Shigemoto R, Nomura S, Mizuno N: Localization of a metabotropic glutamate receptor, mGluR7, in axon terminals of presumed nociceptive, primary afferent fibers in the superficial layers of the spinal dorsal horn: an electron microscope study in the rat. Neurosci Lett 1997; 223: 153-6. https://doi.org/10.1016/S0304-3940(97)13429-2
  29. Azkue J], Mutga M, Fernandez-Capetillo 0, Mateos JM, Elezgarai I, Benitez R, et al: Immunoreactivity for the group III metaborropic glutamate receptor subtype mGluR4a in the superficial laminae of the rat spinal dorsal horn. J Comp Neurol 2001; 430: 448-57. https://doi.org/10.1002/1096-9861(20010219)430:4<448::AID-CNE1042>3.0.CO;2-O
  30. Ohishi H, Nomura S, Ding YQ, Shigemoto R, Wada E, Kinoshita A, et al: Presynaptic localization of a metaborropic glutamate receptor, mGluR7, in the primary afferent neurons: an immunohistochemical study in the rat. Neurosci Lett 1995; 202: 85-8. https://doi.org/10.1016/0304-3940(95)12207-9
  31. Tomiyama M, Kimura T, Maeda T, Tanaka H, Furusawa K, Kurahashi K, et al: Expression of metabotropic glutamate receptor mRNAs in the human spinal cord: implications for selective vulnerability of spinal motor neurons in amyotrophic lateral sclerosis. J Neurol Sci 2001; 189: 65-9. https://doi.org/10.1016/S0022-510X(01)00561-5
  32. Varney MA, Gereau RW 4th: Merabotropic glutamate receptor involvement in models of acute and persistent pain: prospects for the development of novel analgesics. Curr Drug Target eNS Neurol Disord 2002; 1: 283-96. https://doi.org/10.2174/1568007023339300
  33. Nishizuka Y: Studies and perspectives of protein kinase C. Science 1986; 233: 305-12. https://doi.org/10.1126/science.3014651
  34. Yashpal K, Pitcher GM, Parent A, Quirion R, Coderre TJ: Noxious thermal and chemical stimulation induce increases in 3H-phorbol 12,13-dibutyrate binding in spinal cord dorsal horn as well as persistent pain and hyperalgesia, which is reduced by inhibition of protein kinase C. J Neurosci 1995; 15: 3263-72.
  35. Salt TE, Eaton SA: Distinct presynaptic rnerabotropic receptors for L-AP4 and CCG I on GABAergic terminals: pharmacological evidence using novel alpha-methyl derivative mGluR antagonists, MAP4 and MCCG, in the tat thalamus in vivo. Neuroscience 1995; 65: 5-13. https://doi.org/10.1016/0306-4522(94)00464-G
  36. King AE, Liu XH: Dual action of metabotropic glutamate receptor agonists on neuronal excitability and synaptic transmission in spinal ventral horn neurons in vitro. Neurophatmacology 1996; 35: 1673-80. https://doi.org/10.1016/S0028-3908(96)00140-2
  37. Berenbaum MC: What is synergy? Pharmacol Rev 1989; 41: 93-141.
  38. Malmberg AB, Yaksh TL: Pharmacology of the spinal action of ketorolac, morphine, ST-91, U50488H, and L-PIA on the formalin test and an isobolographic analysis of the NSAID interaction. Anesthesiology 1993; 79: 270-81. https://doi.org/10.1097/00000542-199308000-00012
  39. Roerig SC, Fujimoto ]M: Multiplicative interaction between intrathecally and intracerebroventricularly administered mu opioid agonists but limited interactions between delta and kappa agonists for antinociception in mice. ] Pharmacal Exp Ther 1989; 249: 762-8.
  40. Solomon RE, Gebhart GF: Synergistic antinociceptive interactions among drugs administered to the spinal cord. Anesrh Analg 1994;78: 1164-72.