Department of Medicine, Duke University, Durham, NC, USA.
Pain. 2013 Aug;154(8):1295-304. doi: 10.1016/j.pain.2013.04.004. Epub 2013 Apr 6.
Temporomandibular joint disorder (TMJD) is known for its mastication-associated pain. TMJD is medically relevant because of its prevalence, severity, chronicity, the therapy-refractoriness of its pain, and its largely elusive pathogenesis. Against this background, we sought to investigate the pathogenetic contributions of the calcium-permeable TRPV4 ion channel, robustly expressed in the trigeminal ganglion sensory neurons, to TMJ inflammation and pain behavior. We demonstrate here that TRPV4 is critical for TMJ-inflammation-evoked pain behavior in mice and that trigeminal ganglion pronociceptive changes are TRPV4-dependent. As a quantitative metric, bite force was recorded as evidence of masticatory sensitization, in keeping with human translational studies. In Trpv4(-/-) mice with TMJ inflammation, attenuation of bite force was significantly less than in wildtype (WT) mice. Similar effects were seen with systemic application of a specific TRPV4 inhibitor. TMJ inflammation and mandibular bony changes were apparent after injections of complete Freund adjuvant but were remarkably independent of the Trpv4 genotype. It was intriguing that, as a result of TMJ inflammation, WT mice exhibited significant upregulation of TRPV4 and phosphorylated extracellular-signal-regulated kinase (ERK) in TMJ-innervating trigeminal sensory neurons, which were absent in Trpv4(-/-) mice. Mice with genetically-impaired MEK/ERK phosphorylation in neurons showed resistance to reduction of bite force similar to that of Trpv4(-/-) mice. Thus, TRPV4 is necessary for masticatory sensitization in TMJ inflammation and probably functions upstream of MEK/ERK phosphorylation in trigeminal ganglion sensory neurons in vivo. TRPV4 therefore represents a novel pronociceptive target in TMJ inflammation and should be considered a target of interest in human TMJD.
颞下颌关节紊乱（TMJD）以其与咀嚼相关的疼痛而闻名。TMJD 具有普遍性、严重性、慢性、疼痛治疗抵抗性以及发病机制难以捉摸等特点，因此具有重要的医学意义。在此背景下，我们试图研究钙通透性 TRPV4 离子通道在 TMJ 炎症和疼痛行为中的致病作用，该通道在三叉神经节感觉神经元中表达丰富。我们在此证明 TRPV4 对小鼠 TMJ 炎症引起的疼痛行为至关重要，并且三叉神经节的伤害感受变化依赖于 TRPV4。作为一种定量指标，咬合力被记录为咀嚼敏感化的证据，与人类转化研究一致。在 TMJ 炎症的 Trpv4（-/-）小鼠中，咬合力的衰减明显小于野生型（WT）小鼠。用特异性 TRPV4 抑制剂进行全身应用也观察到类似的效果。在注射完全弗氏佐剂后，TMJ 炎症和下颌骨变化明显，但与 Trpv4 基因型明显无关。有趣的是，由于 TMJ 炎症，WT 小鼠在 TMJ 支配的三叉神经感觉神经元中表现出 TRPV4 和磷酸化细胞外信号调节激酶（ERK）的显著上调，而 Trpv4（-/-）小鼠中则没有。神经元中 MEK/ERK 磷酸化遗传受损的小鼠表现出与 Trpv4（-/-）小鼠相似的咬合力降低抵抗，表明 TRPV4 是 TMJ 炎症中咀嚼敏感化所必需的，并且可能在体内三叉神经节感觉神经元中 MEK/ERK 磷酸化的上游起作用。因此，TRPV4 是 TMJ 炎症中伤害感受的新靶点，应被视为人类 TMJD 的潜在治疗靶点。
