Supraspinal delta 2 opioid agonist analgesia in Swiss-Webster mice involves spinal GABA A receptors

Abstract

The tail-flick response is a spinal reflex that can be modulated by administration of antinociceptive agents supraspinally through activation of descending systems and involvement of the action of neurotransmitters in the spinal cord. Descending noradrenergic and serotonergic systems are involved in morphine (and other μ opioid receptor agonists)-induced antinociception. These descending systems, however, are not involved in supraspinal δ opioid receptor agonist-induced antinociception. Recently, a descending system mediated by spinal gamma-aminobutyric acid (GABA) A and B receptors has been demonstrated to be involved in the antinociceptive action of δ 1 opioid receptor agonists ([D-Pen 2,5]enkephalin in ICR mice and [D-Pen 2,5]enkephalin and heroin in Swiss-Webster mice). In the present study, the involvement of spinal GABA A receptors in the antinociceptive action of supraspinal δ 2 opioid receptor agonists, [D-Ser 2]-Leu-enkephalin-Thr and 6-monoacetylmorphine, action was demonstrated. The intrathecal administration of GABA A receptor antagonists, bicuculline and picrotoxin, inhibited the antinociceptive action of both [D-Ser 2]-Leu-enkephalin-Thr and 6-monoacetylmorphine given intracerebroventricularly. The intrathecal administration of 2-hydroxysaclofen, a GABA B receptor antagonist, had no effect. These studies suggest that supraspinal δ 2 like δ 1, opioid receptor action involves spinal GABA A receptors, but δ 2, unlike δ 2, action does not involve GABA B receptors. Thus, the supraspinal δ 1 agonist action (heroin, DPDPE) and the δ 2 agonist action (6MAM, DSLET) can be further differentiated by the selectivity of the spinal GABA receptors involved in Swiss-Webster mice.