Spinal gabapentin and antinociception: mechanisms of action.

Spinal gabapentin has been known to show the antinociceptive effect. Although several assumptions have been suggested, mechanisms of action of gabapentin have not been clearly established. The present study was undertaken to examine the action mechanisms of gabapentin at the spinal level. Male SD rats were prepared for intrathecal catheterization. The effect of gabapentin was assessed in the formalin test. After pretreatment with many classes of drugs, changes of effect of gabapentin were examined. General behaviors were also observed. Intrathecal gabapentin produced a suppression of the phase 2 flinching, but not phase 1 in the formalin test. The antinociceptive action of intrathecal gabapentin was reversed by intrathecal NMDA, AMPA, D-serine, CGS 15943, atropine, and naloxone. No antagonism was seen following administration of bicuculline, saclofen, prazosin, yohimbine, mecamylamine, L-leucine, dihydroergocristine, or thapsigargin. Taken together, intrathecal gabapentin attenuated only the facilitated state. At the spinal level, NMDA receptor, AMPA receptor, nonstrychnine site of NMDA receptor, adenosine receptor, muscarinic receptor, and opioid receptor may be involved in the antinociception of gabapentin, but GABA receptor, L-amino acid transporter, adrenergic receptor, nicotinic receptor, serotonin receptor, or calcium may not be involved.

[1]  S. Childers,et al.  Role of Adenosine Receptors in Spinal G-Protein Activation after Peripheral Nerve Injury , 2002, Anesthesiology.

[2]  B. Piskoun,et al.  Intrathecal administration of liposomal neostigmine prolongs analgesia in mice , 2002, Acta anaesthesiologica Scandinavica.

[3]  A. McKnight,et al.  Block by gabapentin of the facilitation of glutamate release from rat trigeminal nucleus following activation of protein kinase C or adenylyl cyclase , 2001, British journal of pharmacology.

[4]  O. Takahata,et al.  Antinociceptive interaction between spinal clonidine and lidocaine in the rat formalin test: an isobolographic analysis. , 2001, Anesthesia and analgesia.

[5]  B. Chizh,et al.  Antinociception and (R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid antagonism by gabapentin in the rat spinal cord in vivo , 2000, Naunyn-Schmiedeberg's Archives of Pharmacology.

[6]  K. Fink,et al.  Inhibition of neuronal Ca2+ influx by gabapentin and subsequent reduction of neurotransmitter release from rat neocortical slices , 2000, British journal of pharmacology.

[7]  Fahmeed Hyder,et al.  Effects of Gabapentin on Brain GABA, Homocarnosine, and Pyrrolidinone in Epilepsy Patients , 2000, Epilepsia.

[8]  A. Eschalier,et al.  Serotonin receptor subtypes involved in the spinal antinociceptive effect of 5-HT in rats , 2000, Pain.

[9]  M. Shimoyama,et al.  Gabapentin affects glutamatergic excitatory neurotransmission in the rat dorsal horn , 2000, Pain.

[10]  J. Eisenach,et al.  Antiallodynic Effect of Intrathecal Gabapentin and Its Interaction with Clonidine in a Rat Model of Postoperative Pain , 2000, Anesthesiology.

[11]  T. Yaksh,et al.  Evaluation of interaction between gabapentin and ibuprofen on the formalin test in rats. , 1999, Anesthesiology.

[12]  T. Yaksh,et al.  The effect of intrathecal gabapentin on pain behavior and hemodynamics on the formalin test in the rat. , 1999, Anesthesia and analgesia.

[13]  J. Bryans,et al.  Identification of Novel Ligands for the Gabapentin Binding Site on the α2δ Subunit of a Calcium Channel and Their Evaluation as Anticonvulsant Agents , 1998 .

[14]  J. Kocsis,et al.  A summary of mechanistic hypotheses of gabapentin pharmacology , 1998, Epilepsy Research.

[15]  T. Yaksh,et al.  Characterization of the Effects of Gabapentin and 3‐Isobutyl‐gamma‐Aminobutyric Acid on Substance P‐induced Thermal Hyperalgesia , 1998, Anesthesiology.

[16]  A. Dickenson,et al.  Effects of systemic carbamazepine and gabapentin on spinal neuronal responses in spinal nerve ligated rats , 1998, Pain.

[17]  S. McCleary,et al.  Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain. , 1997, The Journal of pharmacology and experimental therapeutics.

[18]  T. Yaksh,et al.  Effect of Subarachnoid Gabapentin on Tactile‐Evoked Allodynia in a Surgically Induced Neuropathic Pain Model in the Rat , 1997, Regional anesthesia.

[19]  K. Elliott,et al.  Spinal gabapentin is antinociceptive in the rat formalin test , 1997, Neuroscience Letters.

[20]  K. Paik,et al.  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 , 1996, Neuroscience Letters.

[21]  D. Oxender,et al.  Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA , 1995, Epilepsy Research.

[22]  E. Lunney,et al.  Transport of Gabapentin, a γ‐Amino Acid Drug, by System L α‐Amino Acid Transporters: A Comparative Study in Astrocytes, Synaptosomes, and CHO Cells , 1995 .

[23]  R. Macdonald,et al.  Gabapentin actions on ligand- and voltage-gated responses in cultured rodent neurons , 1993, Epilepsy Research.

[24]  L. Sorkin,et al.  The role of NMDA and non-NMDA excitatory amino acid receptors in the excitation of primate spinothalamic tract neurons by mechanical, chemical, thermal, and electrical stimuli , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[25]  R. D. Green,et al.  Adenosine A1 and A2 receptors of the substantia gelatinosa are located predominantly on intrinsic neurons: an autoradiography study. , 1988, The Journal of pharmacology and experimental therapeutics.

[26]  T. Yaksh,et al.  Chronic catheterization of the spinal subarachnoid space , 1976, Physiology & Behavior.

[27]  P. Clarenbach,et al.  Gabapentin augments whole blood serotonin in healthy young men , 2005, Journal of Neural Transmission.

[28]  J. Bryans,et al.  Identification of novel ligands for the gabapentin binding site on the alpha2delta subunit of a calcium channel and their evaluation as anticonvulsant agents. , 1998, Journal of medicinal chemistry.