Reduction in ATP-sensitive potassium channel-mediated antinociception in diabetic mice.
To test our hypothesis that the abnormally low efficacy of mu-opioid agonists in diabetic mice may be due to functional changes in ATP-sensitive potassium channels, we evaluated the effects of cromakalim on the tail-flick latencies in diabetic and non-diabetic mice. Anti nociceptive effects of morphine (10 micrograms, ICV) in diabetic mice were significantly less than that in non-diabetic mice. Morphine-induced antinociception in non-diabetic mice was antagonized by pretreatment with glibenclamide (30 micrograms, ICV), an ATP-sensitive potassium channel blocker. Cromakalim (0.3 and 1 micrograms, ICV) produced significant, dose-dependent antinociception in non-diabetic mice, which was significantly reduced by pretreatment with glibenclamide. However, cromakalim did not markedly affect the tail-flick latencies in diabetic mice, even at higher doses (3 micrograms, ICV). On the other hand, [D-Pen2,5]enkephaline (DPDPE, 5 micrograms, ICV), a selective delta-opioid receptor agonist, produced significant antinociception in both diabetic and non-diabetic mice. Since pretreatment with glibenclamide significantly reduced the antinociceptive effect of DPDPE in non-diabetic mice but not in diabetic mice, delta-opioid receptor-mediated antinociception in diabetic mice may be independent of potassium channels. These results suggest that dysfunction of ATP-sensitive potassium channels may contribute to the demonstrated poor antinociceptive response of diabetic mice to mu-opioid agonists.
Kamei
J
J
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
Kawashima
N
N
Narita
M
M
Suzuki
T
T
Misawa
M
M
Kasuya
Y
Y
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D019806:Cromakalim; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000819:agonists; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
D000700:Analgesics; D001578:Benzopyrans; D001786:Blood Glucose; D004745:Enkephalins; D015221:Potassium Channels; D011758:Pyrroles; D017450:Receptors, Opioid, mu; D013757:Tetraethylammonium Compounds; D019806:Cromakalim; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; D000255:Adenosine Triphosphate; D005905:Glyburide