[D-PEN(2)-D-PEN(5)]ENKEPHALIN, A DELTA-OPIOID AGONIST, GIVEN INTRACEREBROVENTRICULARLY IN THE MOUSE PRODUCES ANTINOCICEPTION THROUGH MEDIATION OF SPINAL GABA RECEPTORS

Intracerebroventricular (ICV) administration of [D-Pen(2)-D-Pen(5)]enk ephalin (DPDPE), a delta opioid receptor agonist, activates a descendi ng antinociceptive pathway that inhibits the tail-flick response in mi ce. Involvement of spinal GABA receptors in this response was studied by giving GABA antagonists intrathecally. First, antinociception produ ced by intrathecally administered isoguvacine, a GABA(A) agonist, was inhibited by intrathecal bicuculline (GABA receptor antagonist) or pic rotoxin (chloride channel antagonist). Then, antinociception induced b y ICV DPDPE was antagonized by intrathecal picrotoxin and bicuculline in a dose-and time-dependent manner. Second, intrathecal administratio n of 2-hydroxysaclofen, a GABA(B) antagonist (which inhibited antinoci ception induced by a GABAB agonist, baclofen, given IT), produced a sh ift 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 delta agonist action of DPDPE in the brain leads to activa tion of descending spinal pathways which involve mediation by spinal G ABA(A) and GABA(B) receptors in the antinociceptive response.