Abstract
Development of tolerance in mice pretreated intracerebroventricularly with μ-opioid receptor agonist endomorphin-1, endomorphin-2, or [d-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO) was compared between endomorphin-1- and endomorphin-2-induced antinociception with the tail-flick test. A 2-h pretreatment with endomorphin-1 (30 nmol) produced a 3-fold shift to the right in the dose-response curve for endomorphin-1. Similarly, a 1-h pretreatment with endomorphin-2 (70 nmol) caused a 3.9-fold shift to the right for endomorphin-2. In cross-tolerance experiments, pretreatment with endomorphin-2 (70 nmol) caused a 2.3-fold shift of the dose-response curve for endomorphin-1, whereas pretreatment with endomorphin-1 (30 nmol) caused no change of the endomorphin-2 dose-response curve. Thus, mice acutely tolerant to endomorphin-1 were not cross-tolerant to endomorphin-2, although mice made tolerant to endomorphin-2 were partially cross-tolerant to endomorphin-1; an asymmetric cross-tolerance occurred. Pretreatment with DAMGO 3 h before intracerebroventricular injection of endomorphin-1, endomorphin-2, or DAMGO attenuated markedly the antinociception induced by endomorphin-1 and DAMGO but not endomorphin-2. It is proposed that two separate subtypes of μ-opioid receptors are involved in antinociceptive effects induced by endomorphin-1 and endomorphin-2. One subtype of opioid μ-receptors is stimulated by DAMGO, endomorphin-1, and endomorphin-2, and another subtype of μ-opioidreceptors is stimulated solely by endomorphin-2.
Footnotes
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This work was supported in part by Grant DA 03811 from the National Institutes of Health, National Institute on Drug Abuse (Principal Investigator: L.F.T.). A preliminary report of some of these results will be presented at the 31st Annual Meeting of the Society for Neuroscience, San Diego, CA, November 10–15, 2001.
- Abbreviations:
- i.t.
- intrathecal
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin
- ANOVA
- analysis of variance
- %MPE
- percent maximum possible effect
- Received July 10, 2001.
- Accepted September 6, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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