Dose-dependent antagonism of spinal opioid receptor agonists by naloxone and naltrindole: additional evidence for delta-opioid receptor subtypes in the rat.
Intrathecally administered mu-opioid (morphine; DAMGO ([D-Ala2,N-MePhe4,Gly5-ol]enkephalin)) and delta-opioid (DPDPE ([D-Pen2,D-Pen5] enkephalin); DADLE ([D-Ala2,D-Leu5]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 IC50 being similar for all agonists (2.1-5.4 micrograms). In contrast, the naltrindole antagonist profile was (IC50 in micrograms) 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 mu agonists, the failure of naltrindole to antagonize DADLE suggests that in the rat this peptide acts through a delta site different from that acted upon by DPDPE.
Tiseo
P J
PJ
University of California, Department of Anesthesiology, San Diego, La Jolla 92093.
Yaksh
T L
TL
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology; D066298:In Vitro Techniques; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D000700:Analgesics; D004745:Enkephalins; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; C055382:naltrindole