Abstract
Two highly selective μ-opioid receptor agonists, endomorphin-1 and endomorphin-2, have been identified and postulated to be endogenous μ-opioid receptor ligands. We determined the antinociceptive effects of these two ligands at the supraspinal level in mice with the tail-flick and hot-plate responses. The i.c.v. injection of endomorphin-1 and -2 inhibited the tail-flick and hot-plate responses in a dose-dependent manner. The endomorphin-1 was found to be 3.3- and 2.4-fold more potent than endomorphin-2 in inhibiting the tail-flick and hot-plate responses, respectively. The antinociception induced by endomorphin-1 was blocked by i.c.v. pretreatment with the μ-opioid receptor antagonist β-funaltrexamine but not by the κ-opioid receptor antagonist nor-binaltorphimine, the δ1-opioid antagonist 7-benzylidene naltrexamine, or the δ2-opioid receptor antagonist naltriben. In contrast, the antinociception induced by endomorphin-2 was blocked by i.c.v. pretreatment with β-funaltrexamine or nor-binaltorphimine but not by 7-benzylidene naltrexamine or naltriben. The inhibition of the tail-flick response induced by endomorphin-2 was blocked by pretreatment with an antiserum against dynorphin A(1-17) but not by antisera against Met-enkephalin, Leu-enkephalin, or β-endorphin. None of these antisera reduced the endomorphin-1-induced tail-flick inhibition. We propose that endomorphin-1 produces antinociception by stimulating one type of μ-opioid receptor, whereas endomorphin-2 initially stimulates different μ-opioid receptors, which subsequently induce the release of dynorphins that act on κ-opioid receptors to produce antinociception.
Footnotes
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Send reprint requests to: Leon F. Tseng, Ph.D., Department of Anesthesiology, MEB-462c, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail:ltseng{at}mcw.edu
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↵1 This work was supported in part by Grant DA03811 from the National Institutes of Health, National Institute on Drug Abuse (PI: L.F.T.). A preliminary report of some of the results was presented at the 28th Annual Meeting of the Society for Neuroscience, Los Angeles, CA, November 7–12, 1998 (Tseng et al., 1998).
- Abbreviations:
- β-FNA
- β-funaltrexamine
- NTB
- naltriben
- BNTX
- 7-benzylidene naltrexamine
- nor-BNI
- nor-binaltorphimine
- DPDPE
- [d-Pen2,d-Pen5]enkephalin
- DAMGO
- [d-Ala2,N-MePhe4,Gly-ol5]-enkephalin
- Received April 23, 1999.
- Accepted October 13, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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