Effect of spinal norepinephrine depletion on descending inhibition of the tail flick reflex from the locus coeruleus and lateral reticular nucleus in the rat

Abstract

The lateral reticular nucleus (LRN) and locus coeruleus-subcoeruleus (LC/SC), brainstem structures which overlap the A1 and A6 noradrenergic nuclei respectively, have been implicated in descending modulation of spinal nociceptive transmission. The present studies were designed to examine the role of norepinephrine (NE) in the mediation of inhibition of the nociceptive tail flick reflex produced by focal electrical stimulation in the LRN and LC/SC. Spinal NE was depleted by intrathecal administration of 6-hydroxydopamine (6-OHDA; 20 micrograms) and the threshold electrical stimulation in the LRN and the LC/SC necessary to inhibit the tail flick reflex in lightly pentobarbital-anesthetized rats was determined 9 and 14 days later. Despite a significant depletion (greater than 85%) of lumbar spinal cord NE content, there was no significant change in the tail flick inhibitory stimulation thresholds in the LRN or LC/SC. NE depletion did, however, potentiate the elevation in the inhibitory stimulation threshold in the LRN produced by intrathecal administration of the alpha 2-adrenoceptor antagonist, yohimbine, suggesting that upregulation of spinal adrenoceptors had occurred following 6-OHDA treatment. Adrenoceptor up-regulation was examined quantitatively by characterizing the dose-dependent antinociceptive potency of the selective alpha 2-adrenoceptor agonist clonidine 3, 7, 10, and 14 days following 6-OHDA administration, and analysis of [3H]rauwolscine binding to lumbar spinal cord 9 days following administration of the neurotoxin. The development of supersensitivity, defined as the leftward parallel shift of the dose-response curves for clonidine administered intrathecally, corresponded to the time course of NE depletion following 6-OHDA treatment on the days tested. Binding of [3H]rauwolscine to lumbar spinal cord revealed an elevation in the estimated Bmax without a change in the estimated Kd of the high affinity binding component 9 days following 6-OHDA administration. This study demonstrates that spinal adrenoceptor denervation supersensitivity develops rapidly following intrathecal administration of 6-OHDA and compensates for the selective destruction of spinal noradrenergic nerve terminals. Thus, the absence of effect of NE depletion on the tail flick inhibitory stimulation threshold in the LRN and the LC/SC does not argue against the hypothesis that spinopetal NE-containing neurons in these brainstem loci are involved in modulation of spinal nociceptive transmission.