Abstract
We have investigated the roles of peripheral and central μ, δ, and κ opioid receptors and their subtypes in opioid-induced hypothermia in mice. Measuring rectal temperature after i.p. injection, opioid agonists [morphine, fentanyl, SNC80 ((+)-4-[(αR)-α-((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, β-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 μ1antagonist naloxonazine. The δ2 antagonist naltriben potentiated the hypothermic effect of μ agonists. SNC80-induced hypothermia was blocked by the δ antagonist naltrindole but not by the δ1 antagonist BNTX. Depending on the dose, the δ2 antagonist naltriben produced either a potentiation or an attenuation of the effect of SNC80. U50,488H-induced hypothermia was antagonized by the κ antagonist nor-binaltorphimine but not by acute treatment with the irreversible κ antagonist DIPPA. The peripherally acting opioid loperamide produced hypothermia that could be blocked by several μ-, δ-, or κ-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 μ, κ, and possibly δ opioid receptors after initial activation. In the mediation of δ opioid-induced hypothermia, no clear selectivity between the δ1 and δ2subtypes 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.
Footnotes
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DOI: 10.1124/jpet.102.037655
- Abbreviations:
- BNTX
- 7-benzylidenenaltrexone
- DIPPA
- 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl) ethyl]acetamide
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
- SNC80
- (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoybenzyl]-N,N-diethylbenzamide
- Received April 29, 2002.
- Accepted May 3, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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