Endomorphin-2 Inhibition of Substance P Signaling within Lamina I of the Spinal Cord Is Impaired in Diabetic Neuropathic Pain Rats.
Endomorphin-2 Inhibition of Substance P Signaling within Lamina I of the Spinal Cord Is Impaired in Diabetic Neuropathic Pain Rats.
复制标题
糖尿病神经病理性疼痛大鼠脊髓 I 层内内吗啡肽 2 抑制 P 物质信号传导受损
DOI：
10.3389/fnmol.2016.00167
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发表时间：
2016
影响因子：
4.8
通讯作者：
Li YQ
中科院分区：
文献类型：
--
作者：
Wan FP;Bai Y;Kou ZZ;Zhang T;Li H;Wang YY;Li YQ
糖尿病神经性疼痛（DNP）患者脊髓中阿片类镇痛作用受损，但其原因至今不明。我们推测这是由于脊髓背角内P物质（SP）信号抑制减少所致。为了研究这种可能性，我们评估了内吗啡肽-2（EM 2），一种μ-阿片受体（莫尔）的内源性配体，对DNP大鼠脊髓背角（SDH）I层内SP释放的影响。建立DNP大鼠模型，比较EM 2对炎症痛和DNP大鼠模型的镇痛作用。行为学结果表明，EM 2的镇痛效果在疼痛性糖尿病神经病变的条件下受到损害。然后，我们测量了突触前SP释放不同的刺激方式通过神经激肽-1受体（NK 1 R）的内化。虽然对照组和DNP大鼠之间的基础和诱发SP释放没有显著变化，但EM 2不能抑制DNP中由伤害性机械和热刺激引起的SP释放，但在对照组和炎症疼痛模型中则没有。我们还观察到，EM 2减少SDH I层内FOS阳性神经元的数量，但不改变FOS/NK 1 R双标记神经元的数量。最后，我们通过免疫印迹（WB）和免疫组织化学（IHC）鉴定了初级传入纤维和背根神经节（DRG）神经元内MORs的显著减少。总之，这些数据表明，突触前莫尔表达减少可能是EM 2对SP信号传导的抑制作用丧失的原因，这可能是阿片类药物治疗DNP疗效降低的神经生物学基础之一。
Opiate analgesia in the spinal cord is impaired in diabetic neuropathic pain (DNP), but until now the reason is unknown. We hypothesized that it resulted from a decreased inhibition of substance P (SP) signaling within the dorsal horn of the spinal cord. To investigate this possibility, we evaluated the effects of endomorphin-2 (EM2), an endogenous ligand of the μ-opioid receptor (MOR), on SP release within lamina I of the spinal dorsal horn (SDH) in rats with DNP. We established the DNP rat model and compared the analgesic efficacy of EM2 between inflammation pain and DNP rat models. Behavioral results suggested that the analgesic efficacy of EM2 was compromised in the condition of painful diabetic neuropathy. Then, we measured presynaptic SP release induced by different stimulating modalities via neurokinin-1 receptor (NK1R) internalization. Although there was no significant change in basal and evoked SP release between control and DNP rats, EM2 failed to inhibit SP release by noxious mechanical and thermal stimuli in DNP but not in control and inflammation pain model. We also observed that EM2 decreased the number of FOS-positive neurons within lamina I of the SDH but did not change the amount of FOS/NK1R double-labeled neurons. Finally, we identified a remarkable decrease in MORs within the primary afferent fibers and dorsal root ganglion (DRG) neurons by Western blot (WB) and immunohistochemistry (IHC). Taken together, these data suggest that reduced presynaptic MOR expression might account for the loss of the inhibitory effect of EM2 on SP signaling, which might be one of the neurobiological foundations for decreased opioid efficacy in the treatment of DNP.