delta-opioid receptor agonists produce antinociception and [S-35]GTP gammaS binding in mu receptor knockout mice

We examined the effects of [D-Pen(2),D-Pen(5)]enkephalin (DPDPE), [D-Ala(2) ,Glu(4)]deltorphin (DELT), and (+)-4-[(alpha R)-alpha((2S,5R)-4-Allyl-2,5-d imethyl-1-pipernzinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC80) on [S -35]GTP gamma S binding in brain membranes prepared from mu-opioid receptor knockout(-/-) mice. The potency and maximal response (E-max) of these agon ists were unchanged compared to control mice. In contrast, while the potenc y of [D-Pen(2),pCl-Phe(4),D-Pen(5)]enkephalin (pCl-DPDPE) was not significa ntly different, the E-max was reduced as compared to controls. In the tail- flick test, intracerebroventricular (i.c.v.) or intrathecal (i.th.) DELT pr oduced 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 -/- co mpared 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 th ese agonists require mu-opioid receptors for full activity. However, becaus e DELT mediated G protein activation and antinociception were both comparab le between -/- and wild type mice, we conclude that the mu-opioid receptor is not a critical component of delta-opioid receptor function. (C) 2000 Els evier Science B.V. All rights reserved.