The involvement of alpha 2A-adrenoceptors in morphine analgesia, tolerance and withdrawal in mice.
Alpha(2)-adrenoceptor agonists potentiate opioid analgesia and alleviate opioid withdrawal. The effects of two alpha(2)-adrenoceptor agonists, clonidine (2 mg/kg) and dexmedetomidine (20 and 100 microg/kg), and the alpha(1)-adrenoceptor antagonist prazosin (0.5 mg/kg) were tested on morphine analgesia, tolerance, and withdrawal in wild-type and alpha(2A)-adrenoceptor knock-out (KO) mice. Analgesia and tolerance were assessed with the tail-flick test. Withdrawal was precipitated with naloxone. Prazosin potentiated morphine analgesia equally in both genotypes. Clonidine and dexmedetomidine had no analgesic effects in alpha(2A)-adrenoceptor KO mice, but morphine analgesia and tolerance were similar in both genotypes. Alpha(2A)-Adrenoceptor KO mice exhibited 70% fewer naloxone-precipitated jumps than wild-type mice; weight loss was similar in both genotypes. The alpha(2)-adrenoceptor agonists reduced opioid withdrawal signs only in wild-type mice. We conclude that alpha(2A)-adrenoceptors are not directly involved in morphine analgesia and tolerance, and not critical for potentiation of morphine analgesia by prazosin, but that alpha(2A)-adrenoceptors modulate the expression of opioid withdrawal signs in mice.
Department of Pharmacology and Clinical Pharmacology, University of Turku, Itäinen Pitkäkatu 4, FI-20520 Turku, Finland.
Umit Kazim
UK
Ozdogan
Janne
J
Lähdesmäki
Kristo
K
Hakala
Mika
M
Scheinin
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000378:metabolism*
D000701:Analgesics, Opioid; D018341:Receptors, Adrenergic, alpha-2; D009020:Morphine