D-Pen 2-D-Pen 5]enkephalin, a delta opioid agonist, given intracerebroventricularly in the mouse produces antinociception through mediation of spinal GABA receptors

Abstract

Intracerebroventricular (ICV) administration of [D-Pen 2-D-Pen 5]enkephalin (DPDPE), a δ opioid receptor agonist, activates a descending antinociceptive pathway that inhibits the tail-flick response in mice. Involvement of spinal GABA receptors in this response was studied by giving GABA antagonists intrathecally. First, antinociception produced by intrathecally administered isoguvacine, a GABA A agonist, was inhibited by intrathecal bicuculline (GABA receptor antagonist) or picrotoxin (chloride channel antagonist). Then, antinoniception induced by ICV DPDPE was antagonized by intrathecal picrotoxin and bicuculline in a dose-and time-dependent manner. Second, intrathecal administration of 2-hydroxysaclofen, a GABA B antagonist (which inhibited antinociception induced by a GABA B, agonist, baclofen, given IT), produced a shift of the dose-response curve for ICV DPDPE to the right. GABA A and B antagonists given together intrathecally produced a greater than additive antagonistic effect against ICV DPDPE-induced antinociception. Thus, the δ agonist action of DPDPE in the brain leads to activation of descending spinal pathways which involve mediation by spinal GABA A and GABA B receptors in the antinociceptive response.