Received for publication June 27, 2003.
Revised July 21, 2003.
Accepted for publication September 5, 2003.

Dynorphinergic mechanism mediating endomorphin-2-induced anti-analgesia in the mouse spinal cord

Abstract

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 produces anti-analgesia against opioid agonists-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 prior to 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 anti-analgesic 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 NMDA receptor antagonist MK-801. The EM-2-induced anti-analgesic 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 µ g 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 U50,488H. It is concluded that EM-2 at sub- analgesic doses presumably stimulates a subtype of µ- opioid receptor and subsequently induces the release of dynorphin A(1-17) to produce anti-analgesic effects against µ-, - or -agonists-induced antinociception. The EM-2-induced anti-analgesia 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.

Key words: NMDA receptor, analgesia, anti-analgesia, endomorphins, mouse, opioid

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]