International Journal of Oral Biology

  • 제37권3호
  • /
  • Pages.121-129
  • /
  • 2012
  • /
  • 1226-7155(pISSN)
  • /
  • 2287-6618(eISSN)
대한구강생물학회 (The Korean Academy of Oral Biology)
권호 표지

Glia Dose not Participate in Antinociceptive Effects of Gabapentin in Rats with Trigeminal Neuropathic Pain

  • Yang, Kui-Y. (Department of Oral Physiology, School of Dentistry, Kyungpook National University) ;
  • Kim, Hak-K. (Department of Oral Physiology, School of Dentistry, Kyungpook National University) ;
  • Jin, Myoung-U. (Department of Conservative Dentistry, School of Dentistry, Kyungpook National University) ;
  • Ju, Jin-S. (Department of Oral Physiology, School of Dentistry, Kyungpook National University) ;
  • Ahn, Dong-K. (Department of Oral Physiology, School of Dentistry, Kyungpook National University)
  • 투고 : 2012.08.30
  • 심사 : 2012.09.12
  • 발행 : 2012.09.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Previous clinical studies have demonstrated that gabapentin, a drug that binds to the voltage-gated calcium channel ${\alpha}2{\delta}1$ subunit proteins, is effective in the management of neuropathic pain, but there is limited evidence that addresses the participation of glial cells in the antiallodynic effects of this drug. The present study investigated the participation of glial cells in the anti-nociceptive effects of gabapentin in rats with trigeminal neuropathic pain produced by mal-positioned dental implants. Under anesthesia, the left mandibular second molar was extracted and replaced by a miniature dental implant to induce injury to the inferior alveolar nerve. Mal-positioned dental implants significantly decreased the air-puff thresholds both ipsilateral and contralateral to the injury site. Gabapentin was administered intracisternally beginning on postoperative day (POD) 1 or on POD 7 for three days. Early or late treatment with 0.3, 3, or 30 ${\mu}g$ of gabapentin produced significant anti-allodynic effect in the rats with mal-positioned dental implants. On POD 9, in the mal-positioned dental implants group, OX-42, a microglia marker, and GFAP, an astrocyte marker, were found to be up-regulated in the medullary dorsal horn, compared with the naive group. However, the intracisternal administration of gabapentin (30 ${\mu}g$) failed to reduce the number of activated microglia or astrocytes in the medullary dorsal horn. These findings suggest that gabapentin produces significant antinociceptive effects, which are not mediated by the inhibition of glial cell function in the medullary dorsal horn, in a rat model of trigeminal neuropathic pain.

키워드

참고문헌

  1. Taylor CP, Gee NS, Su TZ, Kocsis JD, Welty DF, Brown JP, Dooley DJ, Boden P, Singh L. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res. 1998;29:233-49.
  2. McLean MJ, Gidal BE. Gabapentin dosing in the treatment of epilepsy. Clin Ther. 2003;25:1382-406.
  3. Levendoglu F, Ogun CO, Ozerbil O, Ogun TC, Ugurlu H. Gabapentin is a first line drug for the treatment of neuropathic pain in spinal cord injury. Spine. 2004;29:743-51.
  4. Singh D, Kennedy DH. The use of gabapentin for the treatment of postherpetic neuralgia. Clin Ther. 2003;25:852-89.
  5. Wodarski R, Clark AK, Grist J, Marchand F, Malcangio M. Gabapentin reverses microglial activation in the spinal cord of streptozotocin-induced diabetic rats. Eur J Pain. 2009;13:807-11.
  6. Tzellos TG, Toulis KA, Goulis DG, Papazisis G, Zampeli VA, Vakfari A, Kouvelas D. Gabapentin and pregabalin in the treatment of fibromyalgia: a systematic review and a meta-analysis. J Clin Pharm Ther. 2010;35:639-56.
  7. Hunter JC, Gogas KR, Hedley LR, Jacobson LO, Kassotakis L, Thompson J, Fontana DJ. The effect of novel anti-epileptic drugs in rat experimental models of acute and chronic pain. Eur J Pharmacol. 1997;324:153-60.
  8. Hwang JH, Yaksh TL. Effect of subarachnoid gabapentin on tactile-evoked allodynia in a surgically induced neuropathic pain model in the rat. Reg Anesth. 1997;22:249-56.
  9. Cheng JK, Pan HL, Eisenach JC. Antiallodynic effect of intrathecal gabapentin and its interaction with clonidine in a rat model of postoperative pain. Anesthesiology. 2000;92:1126-31.
  10. Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem. 1996;271:5768-76.
  11. Fink K, Dooley DJ, Meder WP, Suman-Chauhan N, Duffy S, Clusmann H, Gothert M. Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology. 2002;42:229-36.
  12. Hendrich J, Van Minh AT, Heblich F, Nieto-Rostro M, Watschinger K, Striessnig J, Wratten J, Davies A, Dolphin AC. Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin. Proc Natl Acad Sci USA. 2008;105:3628-33.
  13. Li CY, Song YH, Higuera ES, Luo ZD. Spinal dorsal horn calcium channel alpha2delta-1 subunit upregulation contributes to peripheral nerve injury-induced tactile allodynia. J Neurosci. 2004;24:8494-9.
  14. Melrose HL, Kinloch RA, Cox PJ, Field MJ, Collins D, Williams D. [3H] pregabalin binding is increased in ipsilateral dorsal horn following chronic constriction injury. Neurosci Lett. 2007;417:187-92.
  15. Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. Trends Neurosci. 2001;24:450-5.
  16. Jin SX, Zhuang ZY, Woolf CJ, Ji RR. P38 mitogenactivated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci. 2003;23:4017-22.
  17. Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009;10:23-36.
  18. Piao ZG, Cho IH, Park CK, Hong JP, Choi SY, Lee SJ, Lee S, Park K, Kim JS, Oh SB. Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain. 2006;121:219-31.
  19. Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF, Watkins LR. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain. 2005;115:71-83.
  20. DeLeo JA, Yezierski RP. The role of neuroinflammation and neuroimmune activation in persistent pain. Pain. 2001;90:1-6.
  21. Hanisch UK. Microglia as a source and target of cytokines. Glia. 2002;40:140-155.
  22. Ji RR, Gereau RW 4th, Malcangio M, Strichartz GR. MAP kinase and pain. Brain Res Rev. 2009;60:135-48.
  23. Han SR, Yeo SP, Lee MK, Bae YC, Ahn DK. Early dexamethasone relieves trigeminal neuropathic pain. J Dent Res. 2010;89:915-20.
  24. Lee MK, Han SR, Park MK, Kim MJ, Bae YC, Kim SK, Park JS, Ahn DK. Behavioral evidence for the differential regulation of p-p38 MAPK and p-NF-kappa B in rats with trigeminal neuropathic pain. Mol Pain. 2011;7:57.
  25. Yang CS, Jung CY, Ju JS, Lee MK, Ahn DK. Intracisternal administration of mitogen-activated protein kinase inhibitors reduced IL-1beta-induced mirror-image mechanical allodynia in the orofacial area of rats. Neurosci Lett. 2005;387:32-7.
  26. Jung CY, Choi HS, Ju JS, Park HS, Kwon TG, Bae YC, Ahn DK. Central metabotropic glutamate receptors differentially participate in IL-$1{\beta}$-induced mechanical allodynia in the orofacial area of conscious rats. J Pain. 2006;7:747-56.
  27. Lee MK, Yoon JH, Park MK, Yang GY, Won KA, Park YY, Ahn DK. The intracisternal administration of MEK inhibitor attenuates mechanical and cold allodynia in a rat model of compression of the trigeminal ganglion. Int J Oral Biol. 2010;35:75-81.
  28. Ahn DK, Choi HS, Yeo SP, Woo YW, Lee MK, Yang GY, Jeon HJ, Park JS, Mokha SS. Blockade of central cyclooxygenase (COX) pathways enhances the cannabinoid- induced antinociceptive effects of inflammatory temporomandibular joint (TMJ) nociception. Pain. 2007;132:23-32.
  29. Won KA, Park SH, Kim BK, Baek KS, Yoon DH, Ahn DK. Intracisternal administration of voltage dependent calcium channel blockers attenuates orofacial inflammatory nociceptive behavior in rats. Int J Oral Biol. 2011;36:43-50.
  30. Yaksh TL, Rudy TA. Chronic catheterization of spinal subarachnoid space. Physiol Behav. 1976;17:1031-6.
  31. van Steenberghe D, Lekholm U, Bolender C, Folmer T, Henry P, Herrmann I, Higuchi K, Laney W, Linden U, Astrand P. Applicability of osseointegrated oral implants in the rehabilitation of partial edentulism: a prospective multicenter study on 558 fixtures. Int J Oral Maxillofac Implants. 1990;5:272-81.
  32. Ellies LG. Altered sensation following mandibular implant surgery: a retrospective study. J Prosthet Dent. 1992;68:664-71.
  33. Bartling R, Freeman K, Kraut RA. The incidence of altered sensation of the mental nerve after mandibular implant placement. J Oral Maxillofac Surg. 1999;57:1408-12.
  34. Hegedus F, Diecidue RJ. Trigeminal nerve injuries after mandibular implant placement--practical knowledge for clinicians. Int J Oral Maxillofac Implants. 2006;21:111-6.
  35. Khawaja N, Renton T. Case studies on implant removal influencing the resolution of inferior alveolar nerve injury. Br Dent J. 2009;206:365-70.
  36. Watkins LR, Maier SF. Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov. 2003;2:973-85.
  37. Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007;10:1361-8.
  38. Raghavendra V, Tanga F, DeLeo JA. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther. 2003;306:624-30.
  39. Colburn RW, Rickman AJ, DeLeo JA. The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neurol. 1999;157:289-304.
  40. Beggs S, Salter MW. Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury. Brain Behav Immun. 2007;21:624-33.
  41. Chang YW, Tan A, Saab C, Waxman S. Unilateral focal burn injury is followed by long-lasting bilateral allodynia and neuronal hyperexcitability in spinal cord dorsal horn. J Pain. 2010;11:119-30.
  42. Tsuda M, Inoue K, Salter MW. Neuropathic pain and spinal microglia: a big problem from molecules in "small" glia. Trends Neurosci. 2005;28:101-7.
  43. Watkins LR, Milligan ED, Maier SF. Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain. Adv Exp Med Biol. 2003;521:1-21.
  44. Ren K, Dubner R. Neuron-glia crosstalk gets serious: role in pain hypersensitivity. Curr Opin Anaesthesiol. 2008;21:570-9.
  45. Codderre TJ, Kumar N, Lefebvre CD, Yu JS. Evidence that gabapentin reduces neuropathic pain by inhibiting the spinal release of glutamate. J Neurochem. 2005;94:1131-9.
  46. Boroujerdi A, Zeng J, Sharp K, Kim D, Steward O, Luo ZD. Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states. Pain. 2011;152:649-55.
  47. Sweitzer SM, Schubert P, DeLeo JA. Propentofylline, a glial modulating agent, exhibits antiallodynic properties in a rat model of neuropathic pain. J Pharmacol Exp Ther. 2001;297:1210-7.
  48. Mika J. Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep. 2008;521:1-21.
  49. Okada-Ogawa A, Suzuki I, Sessle BJ, Chiang CY, Salter MW, Dostrovsky JO, Tsuboi Y, Kondo M, Kitagawa J, Kobayashi A, Noma N, Imamura Y, Iwata K. Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms. J Neurosci. 2009;29:11161-71.