Department of Pharmacology, University of Sao Paulo, Sao Paulo, Brazil.
Department of Anatomy, Laboratory of Neuromodulation and Experimental Pain, University of Sao Paulo, Sao Paulo, Brazil.
Pain. 2022 Jul 1;163(7):1414-1423. doi: 10.1097/j.pain.0000000000002527. Epub 2021 Oct 27.
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.
糖尿病性神经病变，常与糖尿病有关，是一种疼痛状态，除了血糖控制外，目前尚无有效的治疗方法。有研究报告称，神经病理性疼痛模型中的大麻素和阿片受体表达水平发生了改变；这些受体的激活可诱导镇痛。我们研究了 CB1R 和阿片受体之间的相互作用是否可以作为治疗糖尿病性神经病变的靶点。为此，我们使用一种减法免疫策略生成了可选择性识别天然 CB1R-MOR 和 CB1R-DOR 异源二聚体的抗体。我们使用链脲佐菌素诱导的糖尿病性神经病变模型评估了 CB1R、MOR、DOR 和相互作用复合物的水平，并检测到与对照组相比，CB1R、MOR、DOR 和 CB1R-MOR 复合物的水平升高。对 G 蛋白信号转导的研究表明，MOR 激动剂而非 DOR 激动剂的活性被 CB1R 配体（包括拮抗剂）的纳摩尔级低剂量增强，这表明 CB1R 配体在 CB1R-MOR 复合物内对 MOR 信号转导具有变构调节作用。由于内源性大麻素肽 hemopressin 显著增强了 MOR 的活性，我们研究了它对机械性痛觉过敏的影响，发现它可阻断野生型小鼠和缺乏 DOR（但有 CB1R-MOR 复合物）的糖尿病性神经病变小鼠的痛觉过敏。然而，hemopressin 不会改变缺乏 DOR 的糖尿病小鼠中 CB1R-MOR 复合物的水平，但会增加缺乏 MOR 的糖尿病小鼠中 CB1R-DOR 复合物的水平。总之，这些结果表明 CB1R-MOR 和 CB1R-DOR 复合物参与了糖尿病性神经病变，并且 hemopressin 可能被开发为治疗这种疼痛状态的潜在治疗方法。
