Abstract
The antinociception induced by i.t. or i.c.v. administration of endomorphins is mediated via μ-opioid receptors. However, although endomorphins do not have an appreciable affinity for κ-opioid receptors, pretreatment with the κ-opioid receptor antagonist norbinaltorphimine markedly reduces the antinociceptive response to i.c.v. or i.t. administered endomorphin-2 but not endomorphin-1. These results suggest that endomorphin-2 initially stimulates μ-opioid receptors, which subsequently induce the release of dynorphins that act on κ-opioid receptors to produce antinociception. The present study was performed in mice to determine whether the release of dynorphins by i.t. administered endomorphin-2 is mediated through μ-opioid receptors to produce antinociception. Intrathecal pretreatment with an antiserum against dynorphin A-(1–17), but not against dynorphin B-(1–13) or α-neoendorphin, dose-dependently prevented the paw-withdrawal inhibition by endomorphin-2. The pretreatments with these antisera did not affect the endomorphin-1- or [d-Ala2,MePhe4,Gly(ol)5]enkephalin-induced paw-withdrawal inhibition. The attenuation of endomorphin-2-induced antinociception by i.t. pretreatment with an antiserum against dynorphin A-(1–17) or s.c. pretreatment with norbinaltorphimine was blocked dose-dependently by s.c. pretreatment with the μ-opioid receptor antagonist β-funaltrexamine or the μ1-opioid receptor antagonist naloxonazine at ultra-low doses that are ineffective against μ-opioid receptor agonists. These results suggest that the spinal antinociception induced by endomorphin-2 is mediated through the stimulation of a distinct subtype of μ1-opioid receptor that induces the release of the endogenous κ-opioid peptide dynorphin A-(1–17) in the spinal cord.
Footnotes
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This work was supported by the Science Research Promotion Fund from the Promotion and Mutual Aid Corporation for Private Schools of Japan, Grants-in-Aid for Scientific Research (C) KAKENHI 16590058 and 17590065 from the Japan Society for the Promotion of Science, and a grant-in-aid for High Technology Research Program from the Ministry of Education, Culture, Sports, Science and Technology Japan.
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doi:10.1124/jpet.105.098293.
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ABBREVIATIONS: DAMGO, [d-Ala2,MePhe4,Gly(ol)5]enkephalin; ANOVA, analysis of variance; TAPA, H-Tyr-d-Arg-Phe-β-Ala-OH.
- Received November 8, 2005.
- Accepted January 3, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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