Diabetic neuropathy, often associated with diabetes mellitus, is a painful condition with no known effective treatment except glycemic control. Studies with neuropathic pain models report alterations in cannabinoid and opioid receptor expression levels; receptors whose activation induce analgesia. We examined whether interactions between CB1R and opioid receptors could be targeted for the treatment of diabetic neuropathy. For this, we generated antibodies that selectively recognize native CB1R-MOR and CB1R-DOR heteromers using a subtractive immunization strategy. We assessed levels of CB1R, MOR, DOR and interacting complexes using a model of streptozotocin-induced diabetic neuropathy, and detected increased levels CB1R, MOR, DOR and CB1R-MOR complexes compared to controls. Examination of G protein signaling revealed that activity induced by the MOR but not the DOR agonist, was potentiated by low nanomolar doses of CB1R ligands including antagonists, suggesting an allosteric modulation of MOR signaling by CB1R ligands within CB1R-MOR complexes. Since the peptide endocannabinoid, hemopressin, caused a significant potentiation of MOR activity, we examined its effect on mechanical allodynia, and found that it blocked allodynia in wild type mice and mice lacking DOR (that have CB1-MOR) with diabetic neuropathy. However, hemopressin does not alter levels of CB1-MOR complexes in diabetic mice lacking DOR but increases levels of CB1-DOR in diabetic mice lacking MOR. Together, these results suggest the involvement of CB1R-MOR and CB1R-DOR complexes in diabetic neuropathy, and that hemopressin could be developed as a potential therapeutic for the treatment of this painful condition.
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