Naltrexone in vivo protects mu receptors from inactivation by beta-funaltrexamine, but not kappa receptors from inactivation by nor-binaltorphimine.
The ability of the competitive opioid antagonist, naltrexone, to protect opioid receptors from inactivation by the nonequilibrium antagonists, beta-funaltrexamine (beta-FNA) and nor-binaltorphimine (nor-BNI), was examined in vivo. Male rats were injected SC with 10 mg/kg naltrexone or saline, 30 min before being injected intracisternally (IC) with water, 10 micrograms beta-FNA, or 1.0 or 10 micrograms nor-BNI. The rats were tested for analgesic responses to either U69,593 (nor-BNI groups) or morphine (beta-FNA groups), on a 50 degrees C hot plate, 24 h later. Morphine produced dose-related increases in the latency to paw lick in rats that received water (IC) (mean ED50 = 3.2 mg/kg). Little or no analgesia occurred after 1.0-30 mg/kg of morphine in animals that had received saline (SC) and 10 micrograms beta-FNA (IC) 24 h earlier. Pretreatment with 10 mg/kg naltrexone attenuated the antagonist effects of beta-FNA (morphine ED50 = 10.8 mg/kg). U69,593 also produced analgesia in animals that received water (IC) (ED50 = 0.97 mg/kg). This analgesia was dose-dependently blocked by nor-BNI for up to 7 days. Naltrexone did not inhibit the actions of nor-BNI. Thus, naltrexone prevented inactivation of mu receptors by beta-FNA but not inactivation of kappa receptors by nor-BNI, suggesting that antagonist interactions with mu receptors are different from those with kappa receptors.
Paronis
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CA
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322.
Waddell
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AB
Holtzman
S G
SG
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides; D002946:Cisterna Magna; D004305:Dose-Response Relationship, Drug; D007267:Injections; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*
D000700:Analgesics; D044482:Benzeneacetamides; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C051844:norbinaltorphimine; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine; C045444:U 69593