Neuronal model of tactile allodynia produced by spinal strychnine: effects of excitatory amino acid receptor antagonists and a mu-opiate receptor agonist.
Touch evoked agitation (allodynia) can be induced by spinal delivery of strychnine and this effect is antagonized by intrathecal NMDA and non-NMDA receptor antagonists, but not by mu-opiate receptor agonists. In this study, we sought to characterize the effect of focal glycine-receptor inhibition on spontaneous and evoked activity in dorsal horn neurons of the chloralose-anesthetized cat. Strychnine (1 mM) applied near the neurons through a dialysis fiber caused an enhanced response to hair deflection, enlargement of the low threshold receptive fields and in some cells, an increase in afterdischarge. These changes were observed only in cells that were activated by both hair deflection and high intensity mechanical stimulation. Subsequent co-administration of an NMDA receptor antagonist (AP-7, 2.0 mM) preferentially blocked strychnine-associated effects without changing the original receptive field characteristics. Co-administration of a non-NMDA excitatory amino acid receptor antagonist (CNQX, 1 mM) with the strychnine served to block low (brush) and high intensity (pinch) afferent input. In contrast, addition of a mu-opiate receptor agonist (alfentanil 2.4 mM) to the strychnine perfusate selectively reduced responsiveness to high intensity stimulation, while having no effect on the exaggerated response to hair deflection. Given the functional and pharmacological similarity of the effects of spinal strychnine to post-nerve injury states in man, disinhibition due to a loss of glycinergic input may be associated with large myelinated fiber-mediated nociceptive states. Consistent with these data is the contention that under normal circumstances, afferent hair follicle input onto convergent neurons is regulated by a tonic glycinergic circuit. Removal of this regulatory influence leads to a magnification of low threshold tactile throughput in dorsal horn. This model may help to provide pharmacological insights into more efficacious treatments for such pain states that are relatively refractory to opioid therapies.
Sorkin
L S
LS
Anesthesiology Research Laboratory, University of California, San Diego 92093-0818, USA. lsorkin@ucsd.edu
Puig
S
S
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D015760:Alfentanil / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002415:Cats; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D018684:Glycine Agents / Q000037:antagonists & inhibitors*; D007278:Injections, Spinal; D008297:Male; D008959:Models, Neurological; D009412:Nerve Fibers / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D011312:Pressure; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012684:Sensory Thresholds / Q000187:drug effects*; D013331:Strychnine / Q000037:antagonists & inhibitors*
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D018684:Glycine Agents; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D015760:Alfentanil; D015763:2-Amino-5-phosphonovalerate; D013331:Strychnine; C031231:2-amino-7-phosphonoheptanoic acid