Supraspinal and spinal delta(2) opioid receptor-mediated antinociceptive synergy is mediated by spinal alpha(2) adrenoceptors

Concurrent administration of low doses of [D-Ala(2),Glu(4)]deltorphin (DELT ) in the spinal cord and rostral ventromedial medulla of the rat produces a synergistic antinociception in the tail-flick test. It was postulated that the synergistic antinociception results from an interaction of the intrath ecally-administered DELT with norepinephrine released in the spinal cord as a result of the microinjection of DELT in the rostral ventromedial medulla . Three approaches were taken to test this hypothesis. The first experiment determined that microinjection of DELT in the rostral ventromedial medulla produced an increase in tail-flick latency that was partially attenuated b y intrathecal administration of the alpha(2)-adrenoceptor antagonist yohimb ine. These data indicated that microinjection of DELT in the medulla causes a release of norepinephrine in the spinal cord. The second experiment dete rmined that intrathecal co-administration of DELT with the alpha(2)-adrenoc eptor agonist dexmedetomidine in a 2:1 fixed dose ratio produced a synergis tic antinociception in the tail-flick test. The final experiment determined that the antinociception produced by concurrent medullary and intrathecal administration of DELT was completely antagonized by intrathecal administra tion of yohimbine. Taken together, these findings support the hypothesis th at the synergistic antinociception produced by concurrent activation of med ullary and spinal delta(2) opioid receptors is mediated, in part, by endoge nous norepinephrine release in the spinal cord. The norepinephrine, acting at alpha(2)-adrenoceptors, interacts in a synergistic manner with intrathec ally administered DELT, acting at spinal delta(2) opioid receptors, to prod uce antinociception. (C) 1999 International Association for the Study of Pa in. Published by Elsevier Science B.V.