Interactions between cannabinoid and opioid receptors in a mouse model of diabetic neuropathy

Abstract

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 induces 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 the levels of CB₁R, MOR, DOR, and interacting complexes using a model of streptozotocin-induced diabetic neuropathy and detected increased levels of CB₁R, MOR, DOR, and CB₁R-MOR complexes compared with those in controls. An 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. Because 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 with diabetic neuropathy lacking DOR (but have CB₁R-MOR complexes). However, hemopressin does not alter the levels of CB₁R-MOR complexes in diabetic mice lacking DOR but increases the levels of CB₁R-DOR complexes 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.

In Brief

Streptozotocin-induced diabetic neuropathy affects the levels of CB₁R-MOR interacting complexes, and this could be targeted by hemopressin for treatment of this painful condition.