title: In vivo activation of a mutant mu-opioid receptor by naltrexone produces a potent analgesic effect but no tolerance: role of mu-receptor activation and delta-receptor blockade in morphine tolerance.
abstract: Opioid analgesics are the standard therapeutic agents for the treatment of pain, but their prolonged use is limited because of the development of tolerance and dependence. Recently, we reported the development of a mu-opioid receptor knock-in (KI) mouse in which the mu-opioid receptor was replaced by a mutant receptor (S196A) using a homologous recombination gene-targeting strategy. In these animals, the opioid antagonist naltrexone elicited antinociceptive effects similar to those of partial agonists acting in wild-type (WT) mice; however, development of tolerance and physical dependence were greatly reduced. In this study, we test the hypothesis that the failure of naltrexone to produce tolerance in these KI mice is attributable to its simultaneous inhibition of delta-opioid receptors and activation of mu-opioid receptors. Simultaneous implantation of a morphine pellet and continuous infusion of the delta-opioid receptor antagonist naltrindole prevented tolerance development to morphine in both WT and KI animals. Moreover, administration of SNC-80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide], a delta agonist, in the naltrexone-pelleted KI animals resulted in a dose-dependent induction in tolerance development to both morphine- and naltrexone-induced analgesia. We conclude that although simultaneous activation of both mu- and delta-opioid receptors results in tolerance development, mu-opioid receptor activation in conjunction with delta-opioid receptor blockade significantly attenuates the development of tolerance.
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA. royxx002@umn.edu
authors.forename: Sabita
authors.initials: S
authors.lastname: Roy
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Guo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kelschenbach
authors.forename: Yuxiu
authors.initials: Y
authors.lastname: Liu
authors.forename: Horace H
authors.initials: HH
authors.lastname: Loh
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D004347:Drug Interactions; D004361:Drug Tolerance / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009020:Morphine / Q000008:administration & dosage* / Q000009:adverse effects; D009271:Naltrexone / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D009294:Narcotics / Q000008:administration & dosage* / Q000009:adverse effects; D010147:Pain Measurement / Q000379:methods; D010879:Piperazines / Q000008:administration & dosage; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000502:physiology*
chemical_list: D001549:Benzamides; D009292:Narcotic Antagonists; D009294:Narcotics; D010879:Piperazines; D017450:Receptors, Opioid, mu; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D009271:Naltrexone; D009020:Morphine; C055382:naltrindole