δ-Opioid receptor agonists produce antinociception and [35S]GTPγS binding in μ receptor knockout mice

Abstract We examined the effects of [ d -Pen 2 , d -Pen 5 ]enkephalin (DPDPE), [ d -Ala 2 ,Glu 4 ]deltorphin (DELT), and (+)-4-[(α R )-α((2 S ,5 R )-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N , N -diethylbenzamide (SNC80) on [ 35 S]GTPγS binding in brain membranes prepared from μ-opioid receptor knockout (−/−) mice. The potency and maximal response ( E max ) of these agonists were unchanged compared to control mice. In contrast, while the potency of [ d -Pen 2 ,pCl-Phe 4 , d -Pen 5 ]enkephalin (pCl-DPDPE) was not significantly different, the E max was reduced as compared to controls. In the tail-flick test, intracerebroventricular (i.c.v.) or intrathecal (i.th.) DELT produced antinociceptive effects in −/− mice with potency that did not differ significantly from controls. In contrast, the antinociceptive potency of i.c.v. and i.th. DPDPE was displaced to the right by 4- and 9-fold in −/− compared to control mice, respectively. Reduced DPDPE antinociceptive potency in −/− mice, taken together with reduced DPDPE- and pCl-DPDPE- stimulated G protein activity in membranes prepared from −/− mice, demonstrate that these agonists require μ-opioid receptors for full activity. However, because DELT mediated G protein activation and antinociception were both comparable between −/− and wild type mice, we conclude that the μ-opioid receptor is not a critical component of δ-opioid receptor function.