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PAIN MEDICINE

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

Department of Pharmacology, Faculty of Medicine, Akdeniz University, Antalya, Turkey

Address correspondence and reprint requests to Arda Tasatargil, MD, Department of Pharmacology, Faculty of Medicine, Akdeniz University, 07070 Antalya, Turkey. Address e-mail to arda{at}med.akdeniz.edu.tr or ardatas@akdeniz.edu.tr.

To test our hypothesis that the abnormally small efficacy of µ-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-Ala², NMePhe⁴, Gly-ol⁵]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 µ-opioid receptor agonist DAMGO (1 µg 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 µg per paw), an NO synthase inhibitor, or methylene blue (500 µg per paw), a guanylyl cyclase inhibitor, significantly decreased DAMGO-induced antinociception in both diabetic and nondiabetic rats. Furthermore, 3-morpholino-sydnonimine (200 µg 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 µ-opioid agonists.

IMPLICATIONS: This is the first study on the role of the nitric oxide (NO)/cyclic guanosine monophosphate pathway on [D-Ala², NMePhe⁴, Gly-ol⁵]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.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999