The antinociceptive effects of a δ-opioid receptor agonist in mice with painful diabetic neuropathy: Involvement of heme oxygenase 1.

Diabetic neuropathy is poorly controlled by classical analgesics and the research of new therapeutic alternatives is indispensable. Our aim is to investigate if treatment with a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer; CORM-2) or an inducible heme oxygenase (HO-1) inducer (cobalt protoporphyrin IX; CoPP) could enhance the antinociceptive effects produced by a δ-opioid receptor (DOR) agonist in mice with painful diabetic neuropathy. In diabetic mice induced by streptozotocin (STZ) injection, the antiallodynic and antihyperalgesic effects produced by the subcutaneous administration of a DOR agonist ([d-Pen(2),d-Pen(5)]-Enkephalin; DPDPE) and the reversion of its effects with the administration of an HO-1 inhibitor (tin protoporphyrin IX; SnPP) were evaluated. Moreover, the antinociceptive effects produced by the intraperitoneal administration of 10mg/kg of CORM-2 or CoPP, alone or combined, with a subanalgesic dose of DPDPE were also assessed. Our results demonstrated that the subcutaneous administration of DPDPE inhibited the mechanical and thermal allodynia as well as the thermal hyperalgesia induced by diabetes in a dose-dependent manner. Moreover, while the antinociceptive effects produced by a low dose of DPDPE were enhanced by CORM-2 or CoPP co-treatments, the inhibitory effects produced by a high dose of DPDPE were completely reversed by the administration of an HO-1 inhibitor, SnPP, indicating the involvement of HO-1 in the antinociceptive effects produced by this DOR agonist during diabetic neuropathic pain in mice. In conclusion, this study shows that the administration of CORM-2 or CoPP combined with a DOR agonist could be an interesting strategy for the treatment of painful diabetic neuropathy.