J Korean Med Sci.  2005 Apr;20(2):307-312. 10.3346/jkms.2005.20.2.307.

Antinociceptive Interactions between Intrathecal Gabapentin and MK801 or NBQX in Rat Formalin Test

• Yoon MH
• Bae HB
• Choi JI

• KMID: 1095209
• DOI: http://doi.org/10.3346/jkms.2005.20.2.307

Abstract

Antagonists for spinal N-methyl-D-aspartate (NMDA) and amino-hydroxy-methtyl-isoxazolepropionate (AMPA) receptors are effective in attenuating acute nociception or injury-induced hyperalgesia. The antinociception of spinal gabapentin is developed in injury-induced hyperalgesia without affecting acute nociception. The authors evaluated the effects of intrathecal gabapentin, NMDA antagonist (MK801) and AMPA antagonist (NBQX) in the formalin test which shows injury-induced hyperalgesia as well as acute pain. We further assessed the interactions between gabapentin and either MK801 or NBQX. Male Sprague-Dawley rats were implanted with intrathecal catheters. To evoke pain, 50 microliter of 5% formalin solution was injected into the hindpaw. The interaction was investigated by a fixed dose analysis or an isobolographic analysis. MK801 and NBQX suppressed flinching responses during phase 1 of the formalin test, while gabapentin had little effect on phase 1. All three agents decreased the phase 2 flinching response. A fixed dose analysis in phase 1 showed that gabapentin potentiated the antinociceptive effect of MK801 and NBQX. Isobolographic analysis in phase 2 revealed a synergistic interaction after coadministration of gabapentin-MK801 or gabapentin-NBQX. Correspondingly, spinal gabapentin with NMDA or AMPA antagonist may be useful in managing acute pain and injury-induced hyperalgesia.

Keyword

Antinociception; gabapentin; Drug Interactions; Injections, Spinal; MK801 Dizocilpine Maleate; NBQX; 2,3-dioxo-6-nitro-7-sultamoylbenzo (f) quinoxaline

MeSH Terms

Amines/administration & dosage/*pharmacology
Analgesics/*pharmacology
Animals
Cyclohexanecarboxylic Acids/administration & dosage/*pharmacology
Dizocilpine Maleate/*pharmacology
Drug Interactions
Excitatory Amino Acid Antagonists/*pharmacology
Hyperalgesia/drug therapy
Injections, Spinal
Male
Quinoxalines/*pharmacology
Rats
Rats, Sprague-Dawley
Receptors, AMPA/drug effects/physiology
Receptors, N-Methyl-D-Aspartate/drug effects/physiology
Research Support, Non-U.S. Gov't
gamma-Aminobutyric Acid/administration & dosage/*pharmacology

Figure

• 

  Fig. 1 Time effect curve of intrathecal gabapentin (A), MK801 (B) and NBQX (C) for flinching response in the formalin test. Each drug was administered 10 min before formalin injection (F). Data are presented as the number of flinches. Each line represents the mean±SEM of 6-8 rats.

• 

  Fig. 2 Dose response curve of intrathecal gabapentin, MK801 and NBQX for flinching response during phase 1 (A) and phase 2 (B) in the formalin test. Data are presented as the total sum of flinches in each phase. Gabapentin reduces flinches in phase 2 but not in phase 1. MK801 and NBQX produce a dose-dependent inhibition of flinches in both phases. Each line represents the mean±SEM of 6-8 rats. Compared with saline or DMSO, *p<0.01, †p<0.001.

• 

  Fig. 3 A fixed dose analysis (A) for the interaction between intrathecal gabapentin (300 µg) and MK 801 during phase 1 and isobologram (B) for the interaction between gabapentin and MK 801 during phase 2 in the formalin test. Data for a fixed dose analysis are presented as the sum of flinches. At a fixed dose analysis, addition of gabapentin to MK 801 was significantly different from that of MK 801 alone, which means that gabapentin increased the antinociception of MK 801. At an isobologram, the ED50 values for each agent are plotted on the x- and y-axes, respectively, and the thick lines represent the S.E.M. of the ED50. The straight line connecting each ED50 value is the theoretical additive line and the point on this line is the theoretical additive ED50. The experimental ED50 point was significantly different from the theoretical ED50 point, indicating a synergistic interaction. Each line represents the mean±SEM of 5-8 rats. Compared with MK 801, *p<0.01, †p<0.001.

• 

  Fig. 4 A fixed dose analysis (A) for the interaction between intrathecal gabapentin (300 µg) and NBQX during phase 1 and isobologram (B) for the interaction between gabapentin and NBQX during phase 2 in the formalin test. Data for a fixed dose analysis are presented as the sum of flinches. At a fixed dose analysis, addition of gabapentin to NBQX was significantly different from that of NBQX alone, which means that gabapentin increased the antinociception of NBQX. At an isobologram, the ED50 values for each agent are plotted on the x- and y-axes, respectively, and the thick lines represent the S.E.M. of the ED50. The straight line connecting each ED50 value is the theoretical additive line and the point on this line is the theoretical additive ED50. The experimental ED50 point was significantly different from the theoretical ED50 point, indicating a synergistic interaction. Each line represents the mean±SEM of 5-7 rats. Compared with NBQX, *p<0.05.

Reference

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. 29:233–249.

2. Kaneko M, Mestre C, Sanchez EH, Hammond DL. Intrathecally administered gabapentin inhibits formalin-evoked nociception and the expression of Fos-like immunoreactivity in the spinal cord of the rat. J Pharmocol Exp Ther. 2000. 292:743–751.

3. Shimoyama N, Shimoyama M, Davis AM, Inturrisi CE, Elliott KJ. Spinal gabapentin is antinociceptive in the rat formalin test. Neurosci Lett. 1997. 222:65–67.

4. Yoon MH, Yaksh TL. The effect of intrathecal gabapentin on pain behavior and hemodynamics on the formalin test in the rat. Anesth Analg. 1999. 89:434–439.

5. Yoon MH, Choi JI, Jeong SW. Spinal gabapentin and antinociception: mechanisms of action. J Korean Med Sci. 2003. 18:255–261.

6. Tolle TR, Berthele A, Schadrack J, Zieglgansberger W. Involvement of glutamatergic neurotransmission and protein kinase C in spinal plasticity and the development of chronic pain. Prog Brain Res. 1996. 110:193–206.

7. Kolhekar R, Meller ST, Gebhart GF. N-methyl-D-aspartate receptor-mediated changes in thermal nociception: allosteric modulation at glycine and polyamine recognition sites. Neuroscience. 1994. 63:925–936.

8. Leem JW, Choi EJ, Park ES, Paik KS. N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor antagonists differentially suppress dorsal horn neuron responses to mechanical stimuli in rats with peripheral nerve injury. Neurosci Lett. 1996. 211:37–40.

9. Mori H, Mishina M. Structure and function of the NMDA receptor channel. Neuropharmacology. 1995. 34:1219–1237.

10. Hamada F, Noutsuka H, Hamada Y, Goto H. Comparison of the spinal anti-nociceptive effects of ES-242-1 and MK-801, two different NMDA antagonists, in rats. Neurosci Res. 2001. 40:61–66.

11. Huang W, Simpson RK Jr. Intrathecal treatment with MK-801 suppresses thermal nociceptive responses and prevents c-fos immunore-activity induced in rat lumbar spinal cord neurons. Neurol Res. 1999. 21:593–598.

12. Hunter JC, Singh L. Role of excitatory amino acid receptors in the mediation of the nociceptive response to formalin in the rat. Neurosci Lett. 1994. 174:217–221.

13. Kristensen JD, Karlsten R, Gordh T, Berge OG. The NMDA antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) has antinociceptive effect after intrathecal injection in the rat. Pain. 1994. 56:59–67.

14. Nishiyama T. Interaction between intrathecal morphine and glutamate receptor antagonists in formalin test. Eur J Pharmacol. 2000. 395:203–210.

15. Nishiyama T, Yaksh TL, Weber E. Effects of intrathecal NMDA and non-NMDA antagonists on acute thermal nociception and their interaction with morphine. Anesthesiology. 1998. 89:715–722.

16. Matthews EA, Dickenson AH. A combination of gabapentin and morphine mediates enhanced inhibitory effects on dorsal horn neuronal responses in a rat model of neuropathy. Anesthesiology. 2002. 96:633–640.

17. Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarachnoid space. Physiol Behav. 1976. 17:1031–1036.

18. Yoon MH, Choi JI, Kwak SH. Characteristics of interactions between intrathecal gabapentin and either clonidine or neostigmine in the formalin test. Anesth Analg. 2004. 98:1374–1379.

19. Tallarida RJ, Murray R.B.. Manual of pharmacologic calculations with computer programs. 1987. 2nd ed. New York: Springer-Verlag.

20. Bryans JS, Davies N, Gee NS, Dissanayake VU, Ratcliffe GS, Horwell DC, Kneen CO, Morrell AI, Oles RJ, O'Toole JC, Perkins GM, Singh L, Suman-Chauhan N, O'Neill JA. Identification of novel ligands for the gabapentin binding site on the alpha2delta subunit of a calcium channel and their evaluation as anticonvulsant agents. J Med Chem. 1998. 41:1838–1845.

21. Benoliel R, Tanaka M, Caudle RM, Iadarola MJ. Co-localization of N-methyl-D-aspartate receptors and substance P (neurokinin-1) receptors in rat spinal cord. Neurosci Lett. 2000. 291:61–64.

22. Jansen KL, Faull RL, Dragunow M, Waldvogel H. Autoradiographic localisation of NMDA, quisqualate and kainic acid receptors in human spinal cord. Neurosci Lett. 1990. 108:53–57.

23. Yaksh TL. The spinal pharmacology of facilitation of afferent processing evoked by high-threshold afferent input of the postinjury pain state. Curr Opin Neurol Neurosurg. 1993. 6:250–256.

24. Furuyama T, Kiyama H, Sato K, Park HT, Maeno H, Takagi H, Tohyama M. Region-specific expression of subunits of ionotropic glutamate receptors (AMPA-type, KA-type and NMDA receptors) in the rat spinal cord with special reference to nociception. Brain Res Mol Brain Res. 1993. 18:141–151.

25. Headley PM, Grillner S. Excitatory amino acids and synaptic transmission: the evidence for a physiological function. Trends Pharmacol Sci. 1990. 11:205–211.

26. Cuesta MC, Arcaya JL, Cano G, Sanchez L, Maixner W, Suarez-Roca H. Opposite modulation of capsaicin-evoked substance P release by glutamate receptors. Neurochem Int. 1999. 35:471–478.

27. Cheng J, Pan H, Eisenach JC. Antiallodynic effect of intrathecal gabapentin and its interaction with clonidine in a rat model of postoperative pain. Anesthesiology. 2000. 92:1126–1131.

28. Hurley RW, Chatterjea D, Rose Feng M, Taylor CP, Hammond DL. Gabapentin and pregabalin can interact synergistically with naproxen to produce antihyperalgesia. Anesthesiology. 2002. 97:1263–1273.

29. Roerig SC, Fujimoto JM. Multiplicative interaction between intrathecally and intracerebroventricularly administered mu opioid agonists but limited interactions between delta and kappa agonists for antinociception in mice. J Pharmacol Exp Ther. 1989. 249:762–768.

30. Gu Y, Huang LY. Gabapentin actions on N-methyl-D-aspartate receptor channels are protein kinase C-dependent. Pain. 2001. 93:85–92.

31. Chen SR, Eisenach JC, McCaslin PP, Pan HL. Synergistic effect between intrathecal non-NMDA antagonist and gabapentin on allodynia induced by spinal nerve ligation in rats. Anesthesiology. 2000. 92:500–506.