advertisement
Abstract #23441 Published in IGR 11-2
Genetic dissection of α(2)-adrenoceptor functions in adrenergic versus nonadrenergic cells
Gilsbach R; Roser C; Beetz N; Brede M; Hadamek K; Haubold M; Leemhuis J; Philipp M; Schneider J; Urbanski MMolecular Pharmacology 2009; 75: 1160-1170
α(2)-Adrenoceptors mediate diverse functions of the sympathetic system and are targets for the treatment of cardiovascular disease, depression, pain, glaucoma, and sympathetic activation during opioid withdrawal. To determine whether α(2)-adrenoceptors on adrenergic neurons or α(2)-adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of α(2)-agonists, we used the dopamine β-hydroxylase (Dbh) promoter to drive expression of α(2A)-adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh-α(2A) transgenic mice were crossed with double knockout mice lacking both α(2A)- and α(2C)-receptors to generate lines with selective expression of α(2A)-autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express α(2A)- and α(2C)-receptors in both adrenergic and nonadrenergic cells, and α(2A)/ α(2C) double-knockout mice, which do not express these receptors in any cell type. We were surprised to find that only a few functions previously ascribed to α(2)-adrenoceptors were mediated by receptors on adrenergic neurons, including feedback inhibition of norepinephrine release from sympathetic nerves and spontaneous locomotor activity. Other agonist effects, including analgesia, hypothermia, sedation, and anesthetic-sparing, were mediated by α(2)-receptors in nonadrenergic cells. In dopamine β-hydroxylase knockout mice lacking norepinephrine, the α(2)-agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of α(2)-adrenoceptor stimulation is not mediated via autoreceptor-mediated inhibition of norepinephrine release. The present study paves the way for a revision of the current view of the α(2)-adrenergic receptors, and it provides important new considerations for future drug development.
L. Hein. Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany. lutz.hein@pharmakol.uni-freiburg.de
Classification:
3.8 Pharmacology (Part of: 3 Laboratory methods)
