Protein kinase C-mediated mu-opioid receptor phosphorylation and desensitization in rats, and its prevention during early diabetes
Protein kinase C-mediated mu-opioid receptor phosphorylation and desensitization in rats, and its prevention during early diabetes
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DOI：
10.1097/j.pain.0000000000000459
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发表时间：
2016-04-01
期刊：
影响因子：
7.4
通讯作者：
Schaefer, Michael
中科院分区：
文献类型：
--
作者：
Mousa, Shaaban A.;Shaqura, Mohammed;Schaefer, Michael
疼痛性糖尿病神经病变与阿片类镇痛受损有关;然而，感觉神经元的确切机制仍不清楚。本研究的目的是确定在早期链脲佐菌素诱导的糖尿病大鼠阿片类药物的反应性改变的可能机制。在这项研究中，我们证明，在糖尿病动物，受损的外周阿片镇痛与减少功能μ阿片受体（莫尔）G蛋白偶联。在链脲佐菌素诱导的糖尿病期间，μ阿片受体免疫反应性神经元与活化形式的蛋白激酶C（PKC）和晚期糖基化终产物（AGEs）受体共定位。此外，莫尔在糖尿病大鼠感觉神经元Thr 370磷酸化，从而脱敏，是由于RAGE依赖的PKC激活。重要的是，使用PKC选择性抑制剂阻断PKC活化、用鞘内siRNA沉默PKC或抑制晚期糖基化终产物（AGE）形成阻止感觉神经元莫尔磷酸化，并因此恢复莫尔G蛋白偶联和镇痛功效。因此，我们的研究结果给出了第一个在体内的证据，RAGE依赖的PKC介导的异源莫尔磷酸化和脱敏的感觉神经元的病理条件下，如糖尿病神经病变。这可能会解开假定的机制，并建议可能的预防策略受损阿片类药物的反应。
Painful diabetic neuropathy is associated with impaired opioid analgesia; however, the precise mechanism in sensory neurons remains unclear. This study aimed to identify putative mechanisms involved in modified opioid responsiveness during early streptozotocin-induced diabetes in rats. In this study, we demonstrate that in diabetic animals, impaired peripheral opioid analgesia is associated with a reduction in functional mu-opioid receptor (MOR) G protein coupling. Mu-opioid receptor immunoreactive neurons colocalized with activated forms of protein kinase C (PKC) and with the receptor for advanced glycation end products (RAGE) during streptozotocin-induced diabetes. Moreover, MOR phosphorylation at Thr370 in sensory neurons of diabetic rats, and thus desensitization, was due to RAGE-dependent PKC activation. Importantly, blocking PKC activation using PKC selective inhibitor, silencing RAGE with intrathecal RAGE siRNA, or inhibiting advanced glycation end product (AGE) formation prevented sensory neuron MOR phosphorylation and, consequently, restored MOR G protein coupling and analgesic efficacy. Thus, our findings give the first in vivo evidence of a RAGE-dependent PKC-mediated heterologous MOR phosphorylation and desensitization in sensory neurons under pathological conditions such as diabetic neuropathy. This may unravel putative mechanisms and suggest possible prevention strategies of impaired opioid responsiveness.