Functional effects of systemically administered agonists and antagonists of μ, δ, and κ opioid receptor subtypes on body temperature in mice

We have investigated the roles of peripheral and central mu, delta, and kappa opioid receptors and their subtypes in opioid-induced hypothermia in mice. Measuring rectal temperature after i.p. injection, opioid agonists [morphine, fentanyl, SNC80 ((+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)3-methoybenzyl]-N,N-diethylbenzamide), U50,488H ((trans-(dl)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide), and loperamide)] were tested alone or with opioid antagonists [naloxone, beta-funaltrexamine, naloxonazine, naltrindole, 7-benzylidenenaltrexone (BNTX), naltriben, nor-binaltorphimine, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide (DIPPA), and methyl-naltrexone] given 15 min after the agonist. All agonists produced dose-related hypothermia, although at low doses, morphine and U50,488H produced hyperthermia. The effects of morphine and fentanyl were antagonized by naloxone and by the mu(1) antagonist naloxonazine. The delta(2) antagonist naltriben potentiated the hypothermic effect of mu agonists. SNC80-induced hypothermia was blocked by the delta antagonist naltrindole but not by the mu(1) antagonist BNTX. Depending on the dose, the delta(2) antagonist naltriben produced either a potentiation or an attenuation of the effect of SNC80. U50,488H-induced hypothermia was antagonized by the kappa antagonist nor-binaltorphimine but not by acute treatment with the irreversible kappa antagonist DIPPA. The peripherally acting opioid loperamide produced hypothermia that could be blocked by several mu-, delta-, or kappa-selective antagonists as well as the peripherally acting antagonist methyl-naltrexone. Methylnaltrexone produced a weak potentiation of morphine-, fentanyl-, and U50,488H-induced hypothermia, whereas a significant attenuation of SNC80-induced hypothermia was observed. In conclusion, at high doses, morphine- and fentanyl- induced hypothermia may involve composite action on mu, kappa, and possibly delta opioid receptors after initial activation. In the mediation of delta opioid-induced hypothermia, no clear selectivity between the delta(1) and delta(2) subtypes was defined. The studies provide new evidence that maintenance of the initial effects of agonist/receptor activation vary with the agonist and the receptor. The existence of both central and peripheral components of opioid-induced hypothermia is also emphasized.