周围降钙素基因相关肽受体的激活与骨关节炎疼痛大鼠模型中关节的机械敏化。
Peripheral calcitonin gene-related peptide receptor activation and mechanical sensitization of the joint in rat models of osteoarthritis pain.
机构信息
University of Nottingham, Nottingham, UK, and University of Nottingham, Sutton Bonington Campus, Sutton Bonington, UK.
出版信息
Arthritis Rheumatol. 2014 Aug;66(8):2188-200. doi: 10.1002/art.38656.
OBJECTIVE
To investigate the role of the sensory neuropeptide calcitonin gene-related peptide (CGRP) in peripheral sensitization in experimental models of osteoarthritis (OA) pain.
METHODS
Experimental knee OA was induced in rats by intraarticular injection of monosodium iodoacetate (MIA) or by transection of the medial meniscus (MMT). Single-unit recordings of joint-innervating nociceptors were obtained in MIA- and saline-treated rats following administration of CGRP or the CGRP receptor antagonist CGRP 8-37. Effects of CGRP 8-37 were also examined in rats that underwent MMT and sham operations. Protein and messenger RNA (mRNA) levels of CGRP receptor components in the L3-L4 dorsal root ganglion (DRG) were investigated following MIA treatment.
RESULTS
In both the MIA and MMT groups, the mechanical sensitivity of joint nociceptors was enhanced compared to that in the control groups. Exogenous CGRP increased mechanical sensitivity in a greater proportion of joint nociceptors in the MIA-treated rats than in the saline-treated rats. Local blockade of endogenous CGRP by CGRP 8-37 reversed both the MIA- and MMT-induced enhancement of joint nociceptor responses. Joint afferent cell bodies coexpressed the receptor for CGRP, called the calcitonin-like receptor (CLR), and the intracellular accessory CGRP receptor component protein. MIA treatment increased the levels of mRNA for CLR in the L3-L4 DRG and the levels of CLR protein in medium and large joint afferent neurons.
CONCLUSION
Our findings provide new and compelling evidence implicating a role of CGRP in peripheral sensitization in experimental OA. Our novel finding of CGRP-mediated control of joint nociceptor mechanosensitivity suggests that the CGRP receptor system may be an important target for the modulation of pain during OA. CGRP receptor antagonists recently developed for migraine pain should be investigated for their efficacy against pain in OA.
目的
研究感觉神经肽降钙素基因相关肽（CGRP）在骨关节炎（OA）疼痛实验模型中周围致敏中的作用。
方法
通过关节内注射单碘乙酸盐（MIA）或内侧半月板（MMT）横切诱导大鼠实验性膝 OA。在 CGRP 或 CGRP 受体拮抗剂 CGRP 8-37 给药后，从 MIA 和盐水处理的大鼠中获得关节传入伤害感受器的单位记录。还在接受 MMT 和假手术的大鼠中检查了 CGRP 8-37 的作用。在 MIA 处理后，研究了 L3-L4 背根神经节（DRG）中 CGRP 受体成分的蛋白和信使 RNA（mRNA）水平。
结果
在 MIA 和 MMT 组中，与对照组相比，关节伤害感受器的机械敏感性增强。与盐水处理的大鼠相比，外源性 CGRP 增加了 MIA 处理大鼠中更大比例的关节伤害感受器的机械敏感性。CGRP 8-37 通过局部阻断内源性 CGRP 逆转了 MIA 和 MMT 诱导的关节伤害感受器反应的增强。关节传入细胞体共表达 CGRP 的受体，称为降钙素样受体（CLR）和细胞内辅助 CGRP 受体成分蛋白。MIA 处理增加了 L3-L4 DRG 中 CLR 的 mRNA 水平和中等和大关节传入神经元中 CLR 蛋白的水平。
结论
我们的研究结果为 CGRP 在实验性 OA 中周围致敏中的作用提供了新的、令人信服的证据。我们关于 CGRP 介导的关节伤害感受器机械敏感性控制的新发现表明，CGRP 受体系统可能是 OA 期间疼痛调节的重要靶点。最近为偏头痛疼痛开发的 CGRP 受体拮抗剂应针对 OA 疼痛的疗效进行研究。
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