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.

糖尿病神经病变通常与糖尿病相关，是一种痛苦的病症，除了血糖控制外，没有已知的有效治疗方法。神经性疼痛模型的研究报告了大麻素和阿片受体表达水平的变化；其激活诱导镇痛的受体。我们研究了 CB ₁ R 和阿片受体之间的相互作用是否可以作为治疗糖尿病神经病变的目标。为此，我们使用消减免疫策略生成了选择性识别天然 CB ₁ R-MOR 和 CB _{1 R-DOR 异聚体的抗体。}我们使用链脲佐菌素诱导的糖尿病神经病变模型评估了 CB ₁ R、MOR、DOR 和相互作用复合物的水平，并检测到与对照组相比， CB ₁ R、MOR、DOR 和 CB ₁ R-MOR 复合物的水平升高。_{G 蛋白信号传导检查显示，低纳摩尔剂量的 CB 1} R 配体（包括拮抗剂）增强了 MOR（而非 DOR 激动剂）诱导的活性，表明 CB 内的 CB 1 R 配体对 MOR 信号传导进行变构_调节1 R-MOR 复合物。由于肽内源性大麻素、升压素可显着增强 MOR 活性，因此我们检查了其对机械异常性疼痛的影响，发现它可以阻断野生型小鼠和缺乏 DOR 的糖尿病神经病变小鼠（但具有 CB 1 R-MOR 复合物）的异常_性疼痛。然而，加压素不会改变缺乏DOR的糖尿病小鼠中的CB _{1 R-MOR复合物的水平，但会增加缺乏MOR的糖尿病小鼠中的CB 1} R-DOR复合物的水平。_{总之，这些结果表明 CB 1} R-MOR 和 CB ₁ R-DOR 复合物参与糖尿病神经病变，并且加压素可以开发为治疗这种疼痛病症的潜在疗法。