Genetic dissection of alpha2-adrenoceptor functions in adrenergic versus nonadrenergic cells.
Alpha(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 alpha(2)-adrenoceptors on adrenergic neurons or alpha(2)-adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of alpha(2)-agonists, we used the dopamine beta-hydroxylase (Dbh) promoter to drive expression of alpha(2A)-adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh-alpha(2A) transgenic mice were crossed with double knockout mice lacking both alpha(2A)- and alpha(2C)-receptors to generate lines with selective expression of alpha(2A)-autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express alpha(2A)- and alpha(2C)-receptors in both adrenergic and nonadrenergic cells, and alpha(2A)/alpha(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 alpha(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 alpha(2)-receptors in nonadrenergic cells. In dopamine beta-hydroxylase knockout mice lacking norepinephrine, the alpha(2)-agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of alpha(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 alpha(2)-adrenergic receptors, and it provides important new considerations for future drug development.
Gilsbach
Ralf
R
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany.
Röser
Christoph
C
Beetz
Nadine
N
Brede
Marc
M
Hadamek
Kerstin
K
Haubold
Miriam
M
Leemhuis
Jost
J
Philipp
Melanie
M
Schneider
Johanna
J
Urbanski
Michal
M
Szabo
Bela
B
Weinshenker
David
D
Hein
Lutz
L
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000502:physiology*; D019076:Transgenes
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D000777:Anesthetics; D006993:Hypnotics and Sedatives; D018341:Receptors, Adrenergic, alpha-2; D009638:Norepinephrine