DIFFERENTIAL ACTIVITIES OF INTRATHECAL MK-801 OR MORPHINE TO ALTER RESPONSES TO THERMAL AND MECHANICAL STIMULI IN NORMAL OR NERVE-INJURED RATS

Nerve ligation injury in rats results in reduced nociceptive and non-n ociceptive thresholds, similar to some aspects of clinical conditions of neuropathic pain. Since underlying mechanisms of hyperalgesia and a llodynia may differ, the present study investigated the pharmacology o f morphine and MK-801 in rats subjected to a tight ligation of the L5 and L6 nerve roots or to a sham-operation procedure. Response to acute nociception was measured by (a) withdrawal of a hindpaw from a radian t heat source, (b) withdrawal of the tail from a radiant heat source o r (c) the latency to a rapid flick of the tail following immersion in water at different noxious temperatures. Mechanical thresholds were de termined by measuring response threshold to probing the hindpaw with v on Frey filaments, Nerve ligation produced a significant, stable and l ong-lasting decrease in threshold to mechanical stimulation (i.e., tac tile allodynia) when compared to sham-operated controls. Standardizati on of the diameter of the filaments (to that of the largest filament) did not alter the response threshold in nerve-injured animals. Nerve l igation produced decreased response latency of the ipsilateral paw (i. e., hyperalgesia) when compared to that of sham-operated rats. Tail-fl ick latencies to thermal stimuli induced by water at constant temperat ures (48 degrees, 52 degrees or 55 degrees C) or by radiant heat were not significantly different between nerve-injured and sham-operated gr oups. At doses which were not behaviorally toxic, MK-801 had no effect on tactile allodynia. At these doses, MK-801 blocked decreased paw wi thdrawal latency to radiant heat in nerve-injured rats, but did not si gnificantly elevate the response threshold of sham-operated rats. Syst emic (i.p.) or intracerebroventricular (i.c.v.) doses of morphine prev iously shown to be antiallodynic in nerve-ligated rats did not affect the response to probing with von Frey filaments in sham-operated contr ols. Intrathecal (i.t.) morphine did not change paw withdrawal thresho lds elicited by von Frey filaments of either nerve-ligated rats (as pr eviously reported) or of sham-operated rats at doses maximally effecti ve against thermal stimuli applied to the tail or foot, Spinal morphin e produced dose-dependent antinociception in both nerve-injured and sh am-operated groups in the foot-flick test but was less potent in the n erve-injured group. Presuppression of hyperalgesia of the foot with i. t. MK-801 in nerve-injured animals did not alter the potency of i.t. m orphine. L.t. morphine was also active in the tail-flick tests with de creased potency in nerve-injured animals and, at some stimulus intensi ties, with a decreased efficacy as well. These data emphasize the dist inction between the inactivity of morphine to suppress mechanical with drawal thresholds (as elicited by von Frey filaments) and the activity of this compound to block the response to an acute thermal nociceptiv e stimulus in sham-operated or nerve-injured rats. It appears that ner ve ligation injury produces a thermal allodynia/hyperalgesia which is likely dependent upon opioid-sensitive small-diameter primary afferent fibers and a mechanical allodynia which may be largely independent of small-fiber input. (C) 1997 International Association for the Study o f Pain. Published by Elsevier Science B.V.