Dose-dependent antagonism of spinal opioid receptor agonists by naloxone and naltrindole: additional evidence for δ-opioid receptor subtypes in the rat

Abstract

Intrathecally administered μ-opioid (morphine; DAMGO ([D-Ala 2,N-MePhe 4,Gly 5-ol]enkephalin)) and δ-opioid (DPDPE ([D-Pen 2,D-Pen 5] enkephalin); DADLE ([D-Ala 2,D-Leu 5]enkephalin)) receptor preferring agonists were systematically challenged with the competitive opiate antagonists naloxone or naltrindole in the rat. Naloxone produced a dose-dependent reduction in agonist effect with the intrathecal IC 50 being similar for all agonists (2.1–5.4 μg). In contrast, the naltrindole antagonist profile was (IC 50 in μg) DPDPE (4.0); morphine (23.5); DADLE ( > 30) and DAMGO ( > 30). Three points are emphasized: (1) antagonism of DPDPE and not DAMGO by naltrindole suggests two distinct opioid sites; (2) a similar potency for naloxone against these agonists suggests that the agonists may act upon spinal sites for which naloxone has comparable affinity or that they may act upon separate sites which are functionally coupled and that the action of naloxone on one or the other site is responsible for the antagonism; and (3) given the modest cross-tolerance between DADLE and μ agonists, the failure of naltrindole to antagonize DADLE suggests that in the rat this peptide acts through a δ site different from that acted upon by DPDPE.