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NEUROPHARMACOLOGY

Possible Involvement of Dynorphin A-(1–17) Release via µ₁-Opioid Receptors in Spinal Antinociception by Endomorphin-2

Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Sendai, Japan (H.M., H.W., T.H., W.S., T.Saw., S.S.); Division of Biochemical Analysis, Central Laboratory of Medical Sciences, Juntendo University School of Medicine, Tokyo, Japan (T.F.); and Department of Biochemistry, Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan (T.Sak.)

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 -opioid receptors, pretreatment with the -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 -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 -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 -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 -opioid peptide dynorphin A-(1–17) in the spinal cord.

Address correspondence to: Dr. Shinobu Sakurada, Tohoku Pharmaceutical University, Department of Physiology and Anatomy, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. E-mail: s-sakura{at}tohoku-pharm.ac.jp

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