ACS Chem Neurosci. 2020 Dec 16;11(24):4376-4386. doi: 10.1021/acschemneuro.0c00622. Epub 2020 Nov 11.
The peripheral mu-opioid receptor (MOR) has been recognized as a potential target to provide safer analgesia with reduced central side effects. Although analgesic incompetence of the peripheral MOR in the absence of inflammation was initially identified more than a decade ago, there has been very limited investigation into the underlying signaling mechanisms. Here we identify that G protein-coupled receptor kinase 2 (GRK2) constitutively interacts with the MOR in peripheral sensory neurons to suppress peripheral MOR activity. Brief exposure to bradykinin (BK) causes uncoupling of GRK2 from the MOR and subsequent restoration of MOR functionality in dorsal root ganglion (DRG) neurons. Interestingly, prolonged BK treatment induces constitutive activation of the MOR through a mechanism that involves protein kinase C (PKC) activation. After silencing Raf kinase inhibitory protein (RKIP) by RNA interference, BK-induced constitutive MOR activation is completely abrogated, which agrees with previous findings that BK activates PKC signaling to initiate GRK2 sequestration by RKIP. Furthermore, we demonstrate that constitutive, peripheral MOR activity requires GRK2 uncoupling and that the FDA-approved SSRI paroxetine promotes this state of uncoupling. Collectively, these results indicate that GRK2 tightly regulates MOR functional states and controls constitutive MOR activity in peripheral sensory neurons, supporting the potential for targeting the kinase to provide safer analgesia.
外周μ-阿片受体（MOR）已被认为是一个潜在的靶点，可以减少中枢副作用，提供更安全的镇痛效果。尽管十多年前就已经初步确定了在没有炎症的情况下外周 MOR 的镇痛能力不足，但对于潜在的信号转导机制的研究非常有限。在这里，我们发现 G 蛋白偶联受体激酶 2（GRK2）在周围感觉神经元中与 MOR 持续相互作用，以抑制外周 MOR 活性。短暂暴露于缓激肽（BK）会导致 GRK2 与 MOR 解偶联，随后背根神经节（DRG）神经元中的 MOR 功能得到恢复。有趣的是，BK 的长期处理通过涉及蛋白激酶 C（PKC）激活的机制诱导 MOR 的组成性激活。通过 RNA 干扰沉默 RKIP（Raf 激酶抑制蛋白）后，BK 诱导的组成性 MOR 激活完全被阻断，这与先前的发现一致，即 BK 通过激活 PKC 信号来启动 RKIP 对 PKC 的隔离。此外，我们证明了组成性外周 MOR 活性需要 GRK2 解偶联，并且已批准的 FDA 药物帕罗西汀可促进这种解偶联状态。总之，这些结果表明 GRK2 严格调节 MOR 的功能状态，并控制周围感觉神经元中的组成性 MOR 活性，支持针对激酶以提供更安全的镇痛效果的潜力。
