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NEUROPHARMACOLOGY

Dynorphinergic Mechanism Mediating Endomorphin-2-Induced Antianalgesia in the Mouse Spinal Cord

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin

We have previously demonstrated that both endomorphin-1 (EM-1) and endomorphin-2 (EM-2) at high doses (1.75–35 nmol) given intrathecally (i.t.) or intracerebroventricularly produce antinociception by stimulation of µ-opioid receptors. Now, we report that EM-2 at small doses (0.05–1.75 nmol), which injected alone did not produce antinociception, produces anti-analgesia against opioid agonist-induced antinociception. The tail-flick (TF) response was used to test the antinociception in male CD-1 mice. Intrathecal pretreatment with EM-2 (0.02–1.75 nmol) 45 min before i.t. morphine (3.0 nmol) injection dose dependently attenuated morphine-induced TF inhibition. On the other hand, a similar dose of EM-1 (1.64 nmol) failed to produce any antianalgesic effect. The EM-2 (1.75 nmol)-produced anti-analgesia against morphine-induced TF inhibition was blocked by i.t. pretreatment with the µ-opioid antagonist naloxone or 3-methoxynaltrexone, but not -opioid receptor antagonist naltrindole, -opioid receptor antagonist nor-binaltorphimine, or N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. The EM-2-induced antianalgesic effect against morphine-induced TF inhibition was blocked by i.t. pretreatment with antiserum against dynorphin A(1-17), but not -endorphin, [Met]-enkephalin, [Leu]-enkephalin, or cholecystokinin antiserum (200 µg each). The i.t. EM-2 pretreatment also attenuated the TF inhibition induced by other µ-opioid agonists, [D-Ala²,N-Me-Phe⁴,Gly-ol⁵]-enkephalin, EM-1 and EM-2, -opioid agonist deltorphin II, and -opioid agonist (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate (U50,488H). It is concluded that EM-2 at subanalgesic doses presumably stimulates a subtype of µ-opioid receptor and subsequently induces the release of dynorphin A(1-17) to produce antianalgesic effects against µ-, -, or -agonists-induced antinociception. The EM-2-induced antianalgesia is not mediated by the release of [Met]-enkephalin, [Leu]-enkephalin, -endorphin, or cholecystokinin, nor does it involve - or -opioid or NMDA receptors in the spinal cord.

Address correspondence to: Dr. Leon F. Tseng, Department of Anesthesiology, Medical College of Wisconsin Medical Education Building, Room M4308, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: ltseng{at}post.its.mcw.edu

This article has been cited by other articles:

				H.-E. Wu, J. Thompson, H.-S. Sun, M. Terashvili, and L. F. Tseng Antianalgesia: Stereoselective Action of dextro-Morphine over levo-Morphine on Glia in the Mouse Spinal Cord J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 1101 - 1108. [Abstract] [Full Text] [PDF]

				M. Terashvili, H.-e. Wu, R. J. Leitermann, H.-S. Sun, A. D. Clithero, and L. F. Tseng Differential Mechanisms of Antianalgesia Induced by Endomorphin-1 and Endomorphin-2 in the Ventral Periaqueductal Gray of the Rat J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 1257 - 1265. [Abstract] [Full Text] [PDF]

				H.-E. Wu, J. Thompson, H.-S. Sun, R. J. Leitermann, J. M. Fujimoto, and L. F. Tseng Nonopioidergic Mechanism Mediating Morphine-Induced Antianalgesia in the Mouse Spinal Cord J. Pharmacol. Exp. Ther., July 1, 2004; 310(1): 240 - 246. [Abstract] [Full Text] [PDF]