Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N4N1, Canada.
Hotchkiss Brain Institute, Cumming School of Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta T2N4N1, Canada.
Sci Signal. 2019 Apr 2;12(575):eaav0711. doi: 10.1126/scisignal.aav0711.
Pain and inflammation are inherently linked responses to injury, infection, or chronic diseases. Given that acute inflammation in humans or mice enhances the analgesic properties of opioids, there is much interest in determining the inflammatory transducers that prime opioid receptor signaling in primary afferent nociceptors. Here, we found that activation of the transient receptor potential vanilloid type 1 (TRPV1) channel stimulated a mitogen-activated protein kinase (MAPK) signaling pathway that was accompanied by the shuttling of the scaffold protein β-arrestin2 to the nucleus. The nuclear translocation of β-arrestin2 in turn prevented its recruitment to the μ-opioid receptor (MOR), the subsequent internalization of agonist-bound MOR, and the suppression of MOR activity that occurs upon receptor desensitization. Using the complete Freund's adjuvant (CFA) inflammatory pain model to examine the role of TRPV1 in regulating endogenous opioid analgesia in mice, we found that naloxone methiodide (Nal-M), a peripherally restricted, nonselective, and competitive opioid receptor antagonist, slowed the recovery from CFA-induced hypersensitivity in wild-type, but not TRPV1-deficient, mice. Furthermore, we showed that inflammation prolonged morphine-induced antinociception in a mouse model of opioid receptor desensitization, a process that depended on TRPV1. Together, our data reveal a TRPV1-mediated signaling pathway that serves as an endogenous pain-resolution mechanism by promoting the nuclear translocation of β-arrestin2 to minimize MOR desensitization. This previously uncharacterized mechanism may underlie the peripheral opioid control of inflammatory pain. Dysregulation of the TRPV1-β-arrestin2 axis may thus contribute to the transition from acute to chronic pain.
疼痛和炎症是机体对损伤、感染或慢性疾病的固有反应。鉴于人类或小鼠的急性炎症增强了阿片类药物的镇痛作用，因此人们非常关注确定使初级传入伤害感受器中的阿片受体信号转导预先致敏的炎症传感器。在这里，我们发现瞬时受体电位香草酸亚型 1（TRPV1）通道的激活刺激了丝裂原活化蛋白激酶（MAPK）信号通路，同时伴随着支架蛋白β-arrestin2向核内易位。β-arrestin2 的核易位反过来阻止了其与μ-阿片受体（MOR）的募集，随后激动剂结合的 MOR 的内化以及 MOR 活性的抑制，这种抑制发生在受体脱敏时。使用完全弗氏佐剂（CFA）炎症性疼痛模型来研究 TRPV1 在调节内源性阿片类镇痛药在小鼠中的作用，我们发现纳洛酮甲碘化物（Nal-M），一种外周受限的、非选择性的、竞争性的阿片受体拮抗剂，在野生型小鼠中减缓了 CFA 诱导的过敏恢复，但在 TRPV1 缺陷型小鼠中没有。此外，我们表明炎症延长了吗啡诱导的阿片受体脱敏小鼠模型中的镇痛作用，该过程依赖于 TRPV1。总之，我们的数据揭示了一种 TRPV1 介导的信号通路，它作为一种内源性疼痛缓解机制，通过促进β-arrestin2 的核易位来最小化 MOR 脱敏。这种以前未被描述的机制可能是外周阿片类药物控制炎症性疼痛的基础。TRPV1-β-arrestin2 轴的失调可能导致从急性疼痛向慢性疼痛的转变。
