Comparative Biology and Experimental Medicine, University of Calgary, Calgary, AB, Canada.
Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
Front Immunol. 2021 Apr 7;12:626884. doi: 10.3389/fimmu.2021.626884. eCollection 2021.
Increased afferent input resulting from painful injury augments the activity of central nociceptive circuits both neuron-neuron and neuron-glia interactions. Microglia, resident immune cells of the central nervous system (CNS), play a crucial role in the pathogenesis of chronic pain. This study provides a framework for understanding how peripheral joint injury signals the CNS to engage spinal microglial responses. During the first week of monosodium iodoacetate (MIA)-induced knee joint injury in male rats, inflammatory and neuropathic pain were characterized by increased firing of peripheral joint afferents. This increased peripheral afferent activity was accompanied by increased Iba1 immunoreactivity within the spinal dorsal horn indicating microglial activation. Pharmacological silencing of C and A afferents with co-injections of QX-314 and bupivacaine, capsaicin, or flagellin prevented the development of mechanical allodynia and spinal microglial activity after MIA injection. Elevated levels of ATP in the cerebrospinal fluid (CSF) and increased expression of the ATP transporter vesicular nucleotide transporter (VNUT) in the ipsilateral spinal dorsal horn were also observed after MIA injections. Selective silencing of primary joint afferents subsequently inhibited ATP release into the CSF. Furthermore, increased spinal microglial reactivity, and alleviation of MIA-induced arthralgia with co-administration of QX-314 with bupivacaine were recapitulated in female rats. Our results demonstrate that early peripheral joint injury activates joint nociceptors, which triggers a central spinal microglial response. Elevation of ATP in the CSF, and spinal expression of VNUT suggest ATP signaling may modulate communication between sensory neurons and spinal microglia at 2 weeks of joint degeneration.
疼痛性损伤引起的传入输入增加增强了中枢伤害感受回路的活动，包括神经元-神经元和神经元-神经胶质相互作用。小胶质细胞是中枢神经系统（CNS）的固有免疫细胞，在慢性疼痛的发病机制中起着关键作用。本研究为理解外周关节损伤如何向中枢神经系统发出信号，使脊髓小胶质细胞产生反应提供了一个框架。在雄性大鼠单碘乙酸（MIA）诱导的膝关节损伤后的第一周，炎症性和神经病理性疼痛的特征是外周关节传入纤维的放电增加。这种外周传入活动的增加伴随着脊髓背角中 Iba1 免疫反应性的增加，表明小胶质细胞的激活。用 QX-314 和布比卡因、辣椒素或鞭毛蛋白共同注射对 C 和 A 传入纤维进行药理学沉默，可防止 MIA 注射后机械性痛觉过敏和脊髓小胶质细胞活性的发展。MIA 注射后还观察到脑脊液（CSF）中 ATP 水平升高和同侧脊髓背角中 ATP 转运体囊泡核苷酸转运体（VNUT）表达增加。初级关节传入纤维的选择性沉默随后抑制了 CSF 中 ATP 的释放。此外，在雌性大鼠中，QX-314 与布比卡因共同给药也可抑制脊髓小胶质细胞的反应性，并缓解 MIA 诱导的关节炎。我们的研究结果表明，早期外周关节损伤激活关节伤害感受器，触发中枢脊髓小胶质细胞反应。CSF 中 ATP 水平升高和脊髓 VNUT 表达增加表明，ATP 信号可能在关节退变 2 周时调节感觉神经元和脊髓小胶质细胞之间的通讯。
