Modification of the expression of naloxone-precipitated withdrawal signs in morphine-dependent mice by diabetes: possible involvement of protein kinase C.
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.
Ohsawa
M
M
Department of Pathophysiology & Therapeutics, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
Kamei
J
J
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002227:Carbazoles; D002273:Carcinogens / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000009:adverse effects*; D009021:Morphine Dependence / Q000201:enzymology / Q000503:physiopathology*; D009270:Naloxone / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000009:adverse effects; D009638:Norepinephrine / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000201:enzymology / Q000503:physiopathology*
D002227:Carbazoles; D002273:Carcinogens; D004791:Enzyme Inhibitors; D007211:Indoles; D009281:Naphthalenes; D009292:Narcotic Antagonists; D009294:Narcotics; D011758:Pyrroles; D009270:Naloxone; D015240:Phorbol 12,13-Dibutyrate; C057416:KT 5720; D009020:Morphine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C058819:calphostin C; D009638:Norepinephrine