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Jpn J Pharmacol. 1999 Mar;79(3):303-11.

Modification of the expression of naloxone-precipitated withdrawal signs in morphine-dependent mice by diabetes: possible involvement of protein kinase C.

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1
Department of Pathophysiology & Therapeutics, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.

Abstract

The involvement of cyclic AMP-dependent protein kinase (PKA) and protein kinase C (PKC) in the modulation of naloxone-precipitated withdrawal jumping in morphine-dependent mice by diabetes was examined. Naloxone-precipitated withdrawal jumps were significantly less in morphine-dependent diabetic mice than in morphine-dependent non-diabetic mice. I.c.v. pretreatment with either calphostin C, a PKC inhibitor, or KT-5720, a PKA inhibitor, attenuated naloxone-precipitated withdrawal jumps in morphine-dependent non-diabetic mice. However, naloxone-precipitated withdrawal jumps in morphine-dependent diabetic mice were not attenuated by i.c.v. pretreatment with either calphostin C or KT5720. Moreover, i.c.v. pretreatment with phorbol-12,13-dibutyrate (PDBu), a PKC activator, attenuated naloxone-precipitated withdrawal jumps in morphine-dependent non-diabetic mice, but not in morphine-dependent diabetic mice. The noradrenaline (NA) turnover in the frontal cortex in morphine-dependent non-diabetic mice, but not in morphine-dependent diabetic mice, was significantly increased 5 min after administration of naloxone. Naloxone-induced enhancement of NA turnover in morphine-dependent non-diabetic mice, but not in morphine-dependent diabetic mice, was blocked by i.c.v. pretreatment with either calphostin C or KT5720 1 hr before naloxone challenge and blocked by PDBu 1 hr before the last injection of morphine. These results suggest that the co-activation of PKC and PKA is needed to elicit naloxone-precipitated withdrawal jumps and enhancement of turnover rate of NA in the frontal cortex in morphine-dependent non-diabetic mice. Furthermore, the attenuation of naloxone-precipitated withdrawal jumps in morphine-dependent diabetic mice may be due, in part, to the desensitization of mu-opioid receptors by the activation of PKC.

PMID:
10230858
DOI:
10.1254/jjp.79.303
[Indexed for MEDLINE]
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