Lack of dependence and rewarding effects of deltorphin II in mu-opioid receptor-deficient mice.
We have previously shown that the antinociceptive effects produced by the delta opioid-selective agonist deltorphin II are preserved in mu-opioid receptor (MOR)-deficient mice. We have now investigated rewarding effects and physical dependence produced by deltorphin II in these animals. Wild-type and MOR-deficient mice were implanted with a cannula into the third ventricle and deltorphin II was administered centrally. The rewarding effects induced by deltorphin II were then investigated using the place preference paradigm. Wild-type mice showed place preference for the compartment previously associated with deltorphin II and this effect was not observed in MOR-deficient mice. In a second experiment, mice received a chronic perfusion of deltorphin II over 6 days, via an Alzet minipump connected to the intraventricular cannula, and withdrawal was precipitated by naloxone administration. Wild-type animals showed a moderate but significant incidence of several somatic signs of withdrawal. This withdrawal response was suppressed in MOR-deficient mice. Analysis of the immunoreactivity levels of PKC-alpha, PKC-beta (I and II) and PKC-gamma isozymes in the cerebral cortex of mice infused chronically with deltorphin II showed a significant up-regulation of all these isozymes in the soluble fraction in wild-type but not in MOR-deficient mice. In conclusion, mu-opioid receptors, which are not involved in deltorphin II antinociception, appear to mediate the effects of chronic deltorphin II on rewarding responses, physical dependence and adaptive changes to PKC.
Hutcheson
D M
DM
Lab de Neurofarmacología, Facultat de Ciences de la Salut I de la Vida, Universitat Pompeu Fabra, Doctor Aiguader, 80, E-08003, Barcelona, Spain.
Matthes
H W
HW
Valjent
E
E
Sánchez-Blázquez
P
P
Rodríguez-Díaz
M
M
Garzón
J
J
Kieffer
B L
BL
Maldonado
R
R
D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology; D003213:Conditioning, Psychological; D015151:Immunoblotting; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000172:deficiency* / Q000235:genetics; D012016:Reference Values; D012201:Reward; D019966:Substance-Related Disorders; D015854:Up-Regulation
D007527:Isoenzymes; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C060209:deltorphin II, Ala(2)-; D011493:Protein Kinase C