Chronic activation of mu- 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 [3H]dopamine from cultured ventral mesencephalic neurons and that of [3H]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 microM] 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 (EC50, 3-6 nM; maximal inhibition about 50%). Moreover, 1.2 mM Ca++ (in the continuous presence of K+) and 100 microM 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 microM) caused an enhanced release of [3H]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-Ala2,MePhe4,Gly-ol5]-enkephalin on the K(+)-induced [3H]noradrenaline release remained unaffected (EC50, 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 microM] or those of cultured locus ceruleus neurons by the alpha-2 adrenoceptor-selective agonist clonidine (1 microM) did not affect K(+)-induced neurotransmitter release upon agonist withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)
Ronken
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Research Institute Neurosciences Vrije Universiteit, Faculty of Medicine, Department of Pharmacology, Amsterdam, The Netherlands.
Mulder
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Schoffelmeer
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AN
D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D002478:Cells, Cultured; D004873:Ergolines / Q000494:pharmacology; D005260:Female; D008125:Locus Coeruleus / Q000502:physiology; D008636:Mesencephalon / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011247:Pregnancy; D019257:Quinpirole; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000502:physiology*; D013378:Substantia Nigra / Q000502:physiology; D017557:Ventral Tegmental Area / Q000502:physiology
D002395:Catecholamines; D004873:Ergolines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D019257:Quinpirole