Masahiro Ohsawa and Junzo Kamei (*)
Department of Pathophysiology & Therapeutics, Faculty of Pharmaceutical
Sciences, Hoshi University, 4-41, Ebara 2-chome, Shinagawa-ku, Tokyo 142-8501,
Japan
(*) To whom correspondence should be addressed.
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.
Keywords: Protein kinase C, Protein kinase A, Morphine withdrawal, Diabetes,
Noradrenaline turnover