Rab7 silencing prevents μ-opioid receptor lysosomal targeting and rescues opioid responsiveness to strengthen diabetic neuropathic pain therapy.
Rab7 silencing prevents μ-opioid receptor lysosomal targeting and rescues opioid responsiveness to strengthen diabetic neuropathic pain therapy.
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作者：
Mousa SA;Shaqura M;Khalefa BI;Zöllner C;Schaad L;Schneider J;Shippenberg TS;Richter JF;Hellweg R;Shakibaei M;Schäfer M
疼痛性糖尿病神经病变通过镇痛剂控制不佳，需要高剂量的阿片类药物，引发副作用并降低患者的生活质量。本研究探讨了Rab 7介导的外周感觉神经元μ-阿片受体（MORs）的溶酶体靶向增强是否是导致链脲佐菌素诱导的糖尿病大鼠阿片类药物反应性降低的原因。在糖尿病动物中，外周阿片类镇痛显著受损与感觉神经元莫尔的丧失和功能性莫尔G蛋白偶联的减少相关。在对照动物中，MORs主要保留在神经元细胞膜上。与此相反，在糖尿病大鼠中，它们与上调的Rab 7在LampI阳性核周溶酶体室中共定位。用鞘内Rab 7-siRNA沉默内源性Rab 7或间接地通过逆转外周感觉神经元中的神经生长因子剥夺来沉默内源性Rab 7不仅阻止了莫尔靶向溶酶体，恢复了它们的质膜密度，而且还挽救了阿片样物质对更好的疼痛缓解的反应。这些发现阐明了体内机制，通过该机制增强Rab 7溶酶体靶向MORs导致糖尿病神经病理性疼痛中阿片类抗伤害感受的丧失。这与炎性疼痛中外周感觉神经元莫尔上调和抗伤害感受相反，并且提供了有趣的证据，即阿片样物质反应性的调节作为疼痛发病机制的函数而变化。
Painful diabetic neuropathy is poorly controlled by analgesics and requires high doses of opioids, triggering side effects and reducing patient quality of life. This study investigated whether enhanced Rab7-mediated lysosomal targeting of peripheral sensory neuron μ-opioid receptors (MORs) is responsible for diminished opioid responsiveness in rats with streptozotocin-induced diabetes. In diabetic animals, significantly impaired peripheral opioid analgesia was associated with a loss in sensory neuron MOR and a reduction in functional MOR G-protein-coupling. In control animals, MORs were retained mainly on the neuronal cell membrane. In contrast, in diabetic rats, they were colocalized with upregulated Rab7 in LampI-positive perinuclear lysosome compartments. Silencing endogenous Rab7 with intrathecal Rab7-siRNA or, indirectly, by reversing nerve growth factor deprivation in peripheral sensory neurons not only prevented MOR targeting to lysosomes, restoring their plasma membrane density, but also rescued opioid responsiveness toward better pain relief. These findings elucidate in vivo the mechanisms by which enhanced Rab7 lysosomal targeting of MORs leads to a loss in opioid antinociception in diabetic neuropathic pain. This is in contrast to peripheral sensory neuron MOR upregulation and antinociception in inflammatory pain, and provides intriguing evidence that regulation of opioid responsiveness varies as a function of pain pathogenesis.
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