Differential Mechanisms of Antianalgesia Induced by Endomorphin-1 and Endomorphin-2 in the Ventral Periaqueductal Gray of the Rat

Authors:
  • HWHsiang-En Wu
    Hsiang-En Wu
  • RLRandy J. Leitermann
    Randy J. Leitermann
  • HSHan-Sen Sun
    Han-Sen Sun
  • ACAndrew D. Clithero
    Andrew D. Clithero
  • LTLeon F. Tseng
    Leon F. Tseng
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Abstract
The effects of pretreatment with endomorphin-1 (EM-1) and endomorphin-2 (EM-2) given into the ventral periaqueductal gray (vPAG) to induce antianalgesia against the tail-flick (TF) inhibition produced by morphine given into the vPAG were studied in rats. Pretreatment with EM-1 (3.5-28 nmol) given into vPAG for 45 min dose-dependently attenuated the TF inhibition produced by morphine (9 nmol) given into vPAG. Similarly, pretreatment with EM-2 (1.7-7.0 nmol) for 45 min also attenuated the TF inhibition induced by morphine; however, a high dose of EM-2 (14 nmol) did not attenuate the morphine-produced TF inhibition. The attenuation of morphine-produced TF inhibition induced by EM-2 or EM-1 pretreatment was blocked by pretreatment with μ-opioid antagonist (-)-naloxone (55 pmol) but not nonopioid (+)-naloxone (55 pmol). However, pretreatment with a morphine-6β-glucuronide-sensitive μ-opioid receptor antagonist 3-methoxynaltrexone (6.4 pmol) selectively blocked EM-2- but not EM-1-induced antianalgesia. Pretreatment with dynorphin A(1-17) antiserum reversed only EM-2- but not EM-1-induced antianalgesia. Pretreatment with antiserum against β-endorphin, [Met5]enkephalin, [Leu5]enkephalin, substance P or cholecystokinin, or with δ-opioid receptor antagonist naltrindole (2.2 nmol) or κ-opioid receptor antagonist norbinaltorphimine (6.6 nmol) did not affect EM-2-induced antianalgesia. It is concluded that EM-2 selectively releases dynorphin A(1-17) by stimulation of a novel subtype of μ-opioid receptor, tentatively designated as μ3 in the vPAG to induce antianalgesia, whereas the antianalgesia induced by EM-1 is mediated by the stimulation of another subtype of μ1- or μ2-opioid receptor.

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