Activation of presynaptic alpha 2-adrenoceptors attenuates the inhibitory effect of mu-opioid receptor agonists on noradrenaline release from brain slices.
3H-noradrenaline release from rat neocortical slices induced by 15 mM K+ was concentration-dependently inhibited by morphine, [D-Ala2-D-Leu5] enkephalin (DADLE) and the calcium entry blocker Cd2+. Blockade of presynaptic alpha 2-adrenoceptors with phentolamine, almost doubling K+-induced 3H-noradrenaline release, slightly enhanced the relative inhibitory effects of morphine and DADLE, whereas that of Cd2+ remained unaffected. In contrast, activation of presynaptic alpha 2-adrenoceptors with clonidine (1 microM) or TL-99 (1 microM), inhibiting release by about 50%, completely abolished the inhibitory effects of morphine and DADLE without affecting that of Cd2+. When in the presence of 1 microM clonidine adenylate cyclase was activated with forskolin (10 microM), which restored release to the drug-free control level, the opioids still did not display their inhibitory effects. Therefore, mu-opioid receptor efficacy appears to be dependent on the degree of activation of alpha 2-adrenoceptors in central noradrenergic nerve terminals, probably through a local receptor interaction within the nerve terminal membrane.
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002104:Cadmium / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D010646:Phentolamine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011957:Receptors, Opioid / Q000378:metabolism*; D017450:Receptors, Opioid, mu
D011942:Receptors, Adrenergic, alpha; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D002104:Cadmium; D005576:Colforsin; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; D003000:Clonidine; D009638:Norepinephrine; D010646:Phentolamine