Differential mechanisms of antianalgesia induced by endomorphin-1 and endomorphin-2 in the ventral periaqueductal gray of the rat.
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 mu-opioid antagonist (-)-naloxone (55 pmol) but not nonopioid (+)-naloxone (55 pmol). However, pretreatment with a morphine-6beta-glucuronide-sensitive mu-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 beta-endorphin, [Met(5)]enkephalin, [Leu(5)]enkephalin, substance P or cholecystokinin, or with delta-opioid receptor antagonist naltrindole (2.2 nmol) or kappa-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 mu-opioid receptor, tentatively designated as mu(3) in the vPAG to induce antianalgesia, whereas the antianalgesia induced by EM-1 is mediated by the stimulation of another subtype of mu(1)- or mu(2)-opioid receptor.
Terashvili
Maia
M
Department of Anesthesiology, Medical College of Wisconsin, Medical Education Building, Room M4308, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA.
Wu
Hsiang-En
HE
Leitermann
Randy J
RJ
Sun
Han-Sen
HS
Clithero
Andrew D
AD
Tseng
Leon F
LF
D000698:Analgesia; D000818:Animals; D002766:Cholecystokinin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000378:metabolism; D004743:Enkephalin, Leucine / Q000378:metabolism; D004744:Enkephalin, Methionine / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors; D009270:Naloxone / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D010487:Periaqueductal Gray / Q000187:drug effects*; D051381:Rats; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013373:Substance P / Q000378:metabolism; D001615:beta-Endorphin / Q000378:metabolism
D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D013373:Substance P; D009270:Naloxone; C105294:endomorphin 2; D004744:Enkephalin, Methionine; D004743:Enkephalin, Leucine; D001615:beta-Endorphin; D004399:Dynorphins; D009020:Morphine; D002766:Cholecystokinin