Effects of a mu-opioid receptor agonist on G-protein activation in streptozotocin-induced diabetic mice.
Many clinical and experimental studies have suggested that diabetes or hyperglycemia alter pain sensitivity, and sensitivity to several drugs. It has been reported that the antinociceptive potency of morphine is decreased in several rodent models of hyperglycemia, including streptozotocin-induced diabetes, an animal models of type I diabetes. The present study was designed to investigate in streptozotocin-induced diabetic mice the effect of the selective micro-opioid agonist [D-Ala(2), NMePhe(4), Gly-ol(5)]enkephalin (DAMGO) on G-protein activation by monitoring guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding to pons/medulla membranes, which contain the key areas for opioid antinociception. In the tail-flick test, DAMGO (1-10 ng, intracerebroventricularly) produced a marked dose-dependent antinociception in non-diabetic mice. In streptozotocin-induced diabetic mice, the effect of DAMGO was significantly attenuated as compared to that in non-diabetic mice. In the [35S]GTPgammaS binding assay, DAMGO (0.1-10 microM) increased the binding of [35S]GTPgammaS to pons/medulla membranes from non-diabetic mice in a concentration-dependent manner, affording approximately 100% maximal stimulation at 10 microM. The maximal stimulation of [35S]GTPgammaS binding by DAMGO (10 microM) in streptozotocin-induced diabetic mice (100.55+/-3.12%), was similar to non-diabetic mice. The present results indicated that the antinociceptive effect of DAMGO given supraspinally was less potent in streptozotocin-induced diabetic mice than that in non-diabetic mice, whereas the mu-opioid receptor-mediated G-protein activation in pons/medulla was unaltered in streptozotocin-induced diabetic mice. Thus, the attenuation of DAMGO-induced antinociception in streptozotocin-induced diabetic mice is probably caused by dysfunction in cellular pathways after the activation of G-proteins.
Ohsawa
M
M
Department of Anesthesiology, Medical College of Wisconsin, Medical Education Building, Room 462c, 8701 Watertown Plank Road, 53226, Milwaukee, WI, USA.
Mizoguchi
H
H
Narita
M
M
Kamei
J
J
Nagase
H
H
Tseng
L F
LF
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement; D011149:Pons / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013462:Sulfur Radioisotopes
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D013462:Sulfur Radioisotopes; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019204:GTP-Binding Proteins