Reduction in [D-Ala2, NMePhe4, Gly-ol5]enkephalin-induced peripheral antinociception in diabetic rats: the role of the L-arginine/nitric oxide/cyclic guanosine monophosphate pathway.
To test our hypothesis that the abnormally small efficacy of mu-opioid agonists in diabetic rats may be due to functional changes in the L-arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway, we evaluated the effects of N-iminoethyl-L-ornithine, methylene blue, and 3-morpholino-sydnonimine on [D-Ala(2), NMePhe(4), Gly-ol(5)]enkephalin (DAMGO)-induced antinociception in both streptozotocin (STZ)-diabetic and nondiabetic rats. Animals were rendered diabetic by an injection of STZ (60 mg/kg intraperitoneally). Antinociception was evaluated by the formalin test. The mu-opioid receptor agonist DAMGO (1 microg per paw) suppressed the agitation response in the second phase. The antinociceptive effect of DAMGO in STZ-diabetic rats was significantly less than in nondiabetic rats. N-Iminoethyl-L-ornithine (100 microg per paw), an NO synthase inhibitor, or methylene blue (500 microg per paw), a guanylyl cyclase inhibitor, significantly decreased DAMGO-induced antinociception in both diabetic and nondiabetic rats. Furthermore, 3-morpholino-sydnonimine (200 microg per paw), an NO donor, enhanced the antinociceptive effect of DAMGO in nondiabetic rats but did not change in diabetic rats. These results suggest that the peripheral antinociceptive effect of DAMGO may result from activation of the L-arginine/NO/cGMP pathway and dysfunction of this pathway; also, events that are followed by cGMP activation may have contributed to the demonstrated poor antinociceptive response of diabetic rats to mu-opioid agonists.


CONCLUSIONS
This is the first study on the role of the nitric oxide (NO)/cyclic guanosine monophosphate pathway on [D-Ala(2), NMePhe(4), Gly-ol(5)]enkephalin (DAMGO)-induced peripheral antinociception and the effect of diabetes on this pathway. The study suggests a possible role of DAMGO as a peripherally-acting analgesic drug.
Tasatargil
Arda
A
Department of Pharmacology, Faculty of Medicine, Akdeniz University, Antalya, Turkey.
Sadan
Gulay
G
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000502:physiology*; D001786:Blood Glucose / Q000378:metabolism; D006152:Cyclic GMP / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005557:Formaldehyde; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000701:Analgesics, Opioid; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005557:Formaldehyde; D009569:Nitric Oxide; C002385:linsidomine; D001120:Arginine; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D008751:Methylene Blue