Gabapentin decreases the level of glutamate and elevates that of garmma-amino-butyric acid in the central nervous system. Gabapentin was shown to have antinociceptive effects in several facilitated pain models. Intrathecal gabapentin was also known to be effective in reducing mechanical allodynia in animals with neuropathic pain. In this study, we investigated to see whether intrathecal gabapentin produces antihyperalgesic effects on thermal and mechanical hyperalgesia in neuropathic rats and whether its effects are associated with motor impairment. To induce neuropathic pain in Sprague-Dawley rats, left L5 and L6 spinal nerves were ligated. After a week, lumbar catheterization into subarachnoid space was performed. Then, paw withdrawal times to thermal stimuli and vocalization thresholds to paw pressure were determined before and up to 2 hr after intrathecal injection of gabapentin. Also, motor functions including performance times on rota-rod were determined. Intrathecal gabapentin attenuated significantly thermal and mechanical hyperalgesia in neuropathic rats, but did not block thermal and mechanical nociception in sham-operated rats. Intrathecal gabapentin of antihyperalgesic doses inhibited motor coordination performance without evident ambulatory dysfunction. This study demonstrates that intrathecal gabapentin is effective against thermal and mechanical hyperalgesia, in spite of moderate impairment of motor coordination.
Acetic Acids/administration & dosage/*pharmacology ; *Amines ; Analgesics/administration & dosage/*pharmacology ; Animals ; *Cyclohexanecarboxylic Acids ; Dose-Response Relationship, Drug ; Injections, Spinal ; Ligation ; Male ; Rats ; Rats, Sprague-Dawley ; Spinal Nerves/*injuries ; Time Factors ; *gamma-Aminobutyric Acid

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.
Acetic Acids/administration & dosage ; Acetic Acids/metabolism ; Acetic Acids/pharmacology* ; Adrenergic Antagonists/metabolism ; Adrenergic alpha-Antagonists/metabolism ; Analgesics/administration & dosage ; Analgesics/metabolism ; Analgesics/pharmacology* ; Animals ; Atropine/metabolism ; Dihydroergocristine/metabolism ; Enzyme Inhibitors/metabolism ; Excitatory Amino Acid Agonists/metabolism ; GABA Antagonists/metabolism ; Injections, Spinal ; Leucine/metabolism ; Male ; Mecamylamine/metabolism ; Muscarinic Antagonists/metabolism ; N-Methylaspartate/metabolism ; Naloxone/metabolism ; Narcotic Antagonists/metabolism ; Nicotinic Antagonists/metabolism ; Pain Measurement ; Quinazolines/metabolism ; Rats ; Rats, Sprague-Dawley ; Serine/metabolism ; Spinal Cord/drug effects* ; Thapsigargin/metabolism ; Triazoles/metabolism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism