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Functional effects of systemically administered agonists and antagonists of mu, delta, and kappa opioid receptor subtypes on body temperature in mice.
J Pharmacol Exp Ther. 2002 Sep; 302(3):1253-64.JP

Abstract

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 delta(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. Methyl-naltrexone 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.

Authors+Show Affiliations

CNS Discovery Research, Janssen Research Foundation, Turnhoutseweg 30, B-2340 Beerse, Belgium. ABAKER5@janbe.jnj.comNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12183687

Citation

Baker, Alexis K., and Theo F. Meert. "Functional Effects of Systemically Administered Agonists and Antagonists of Mu, Delta, and Kappa Opioid Receptor Subtypes On Body Temperature in Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 302, no. 3, 2002, pp. 1253-64.
Baker AK, Meert TF. Functional effects of systemically administered agonists and antagonists of mu, delta, and kappa opioid receptor subtypes on body temperature in mice. J Pharmacol Exp Ther. 2002;302(3):1253-64.
Baker, A. K., & Meert, T. F. (2002). Functional effects of systemically administered agonists and antagonists of mu, delta, and kappa opioid receptor subtypes on body temperature in mice. The Journal of Pharmacology and Experimental Therapeutics, 302(3), 1253-64.
Baker AK, Meert TF. Functional Effects of Systemically Administered Agonists and Antagonists of Mu, Delta, and Kappa Opioid Receptor Subtypes On Body Temperature in Mice. J Pharmacol Exp Ther. 2002;302(3):1253-64. PubMed PMID: 12183687.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional effects of systemically administered agonists and antagonists of mu, delta, and kappa opioid receptor subtypes on body temperature in mice. AU - Baker,Alexis K, AU - Meert,Theo F, PY - 2002/8/17/pubmed PY - 2002/9/19/medline PY - 2002/8/17/entrez SP - 1253 EP - 64 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 302 IS - 3 N2 - 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 delta(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. Methyl-naltrexone 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12183687/Functional_effects_of_systemically_administered_agonists_and_antagonists_of_mu_delta_and_kappa_opioid_receptor_subtypes_on_body_temperature_in_mice_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12183687 DB - PRIME DP - Unbound Medicine ER -