CHRONIC ACTIVATION OF MU-OPIOID AND KAPPA-OPIOID RECEPTORS IN CULTURED CATECHOLAMINERGIC NEURONS FROM RAT-BRAIN CAUSES NEURONAL SUPERSENSITIVITY WITHOUT RECEPTOR DESENSITIZATION

The effects of chronic activation of mu- and kappa-opioid receptors on the release of [H-3]dopamine from cultured ventral mesencephalic neurons and that of [H-3]noradrenaline from cultured locus ceruleus neurons were studied. It was found that a 4-day exposure of cultured mesencephalic neurons to the kappa-agonist U69,593 {(5 alpha,7 alpha,8 beta)-(-)-N-methyl-N-[7(1-pyrrolidinyl)-1-oxaspiro(4,5)-dec-8-yl]benzeneacetamide; 1 mu M} increased markedly 25 mM K+-induced dopamine release upon opioid withdrawal by about 70%, with no change in the release-inhibitory effects of U69,593 (EC(50), 3-6 nM; maximal inhibition about 50%). Moreover, 1.2 mM Ca++ (in the continuous presence of K+) and 100 mu M N-methyl-D-aspartic acid receptor-mediated dopamine release also was potentiated to a similar extent after chronic kappa receptor activation. Similarly, 4-day treatment of cultured locus ceruleus neurons with morphine (1 mu M) caused an enhanced release of [H-3]noradrenaline induced by K+, Ca++ or N-methyl-D-aspartic acid upon opioid withdrawal by 55 to 150%. In addition, the release-inhibitory effect of the mu-selective agonist [D-Ala(2),MePhe(4),Gly-ol(5)]-enkephalin on the K+-induced [H-3]noradrenaline release remained unaffected (EC(50), 10-12 nM; maximal effect, 80-90%). Interestingly, chronic activation of autoreceptors on cultured mesencephalic neurons by the dopamine D-2 receptor-selective agonist LY171,555 {(trans)-(-)-(4aR)4,4a,5 ,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4g}quinoline; 1 mu M} or those of cultured locus ceruleus neurons by the alpha-2 adrenoceptor-selective agonist clonidine (1 mu M) did not affect K+-induced neurotransmitter release upon agonist withdrawal. Thus, chronic activation of opioid receptors on cultured catecholaminergic neurons, unlike that of autoreceptors, induces neuronal supersensitivity upon opioid withdrawal, i.e., an increased sensitivity toward stimuli without apparent changes in opioid receptor efficacy. This functional feature of opioid receptors may be particularly important in the acquisition and maintenance of drug dependence.