ABSTRACT
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.
Subject(s)
Animals , Male , Rats , Acetates/administration & dosage , Acetates/metabolism , Acetates/pharmacology , Adrenergic Antagonists/metabolism , Adrenergic alpha-Antagonists/metabolism , Analgesics/administration & dosage , Analgesics/metabolism , Analgesics/pharmacology , Atropine/metabolism , Dihydroergocristine/metabolism , Enzyme Inhibitors/metabolism , Excitatory Amino Acid Agonists/metabolism , GABA Antagonists/metabolism , Injections, Spinal , Leucine/metabolism , Mecamylamine/metabolism , Muscarinic Antagonists/metabolism , N-Methylaspartate/metabolism , Naloxone/metabolism , Narcotic Antagonists/metabolism , Nicotinic Antagonists/metabolism , Pain Measurement , Quinazolines/metabolism , Rats, Sprague-Dawley , Serine/metabolism , Spinal Cord/drug effects , Thapsigargin/metabolism , Triazoles/metabolism , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolismABSTRACT
Multiple episodes of blood-brain barrier disruption were induced by sequential intraspinal injections of ethidium bromide. In addition to the barrier disruption, there was toxic demyelination and exposure of myelin components to the immune system. Twenty-seven 3-month-old Wistar rats received 2, 3 or 4 injections of 1 mul of either 0.1 percent ethidium bromide in normal saline (19 rats) or 0.9 percent saline (8 rats) at different levels of the spinal cord. The time intervals between the injections ranged from 28 to 42 days. Ten days after the last injection, all rats were perfused with 2.5 percent glutaraldehyde. The spinal sections were evaluated macroscopically and by light and transmission electron microscopy. All the lesions demonstrated a mononuclear phagocytic infiltrate apparently removing myelin. Lymphocytes were not conspicuos and were found in only 34 percent of the lesions. No perivascular cuffings were detected. In older lesions (38 days and older) they were found only within Virchow-Robin spaces. This result suggests that multiple blood-brain barrier disruptions with demyelination and exposure of myelin components to the immune system were not sufficient to induce an immune-mediated reaction in the central nervous system.