The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, Hubei Province, China.
Department of Oral and Maxillofacial Trauma and Temporomandibular Joint Surgery, Hubei-MOST KLOS & KLOBM, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
Mol Neurobiol. 2023 Nov;60(11):6264-6274. doi: 10.1007/s12035-023-03462-0. Epub 2023 Jul 13.
Pain is one of the main reasons for patients with temporomandibular joint (TMJ) disorders seeking medical care. However, there is no effective treatment yet as its mechanism remains unclear. Herein, we found that the injection of monoiodoacetate (MIA) into mice TMJs can induce typical joint pain as early as 3 days, accompanied by an increased percentage of calcitonin gene-related peptide positive (CGRP) neurons and isolectin B4 positive (IB4) in the trigeminal ganglions (TGs). Our previous study has discovered that alpha-kinase 1 (ALPK1) may be involved in joint pain. Here, we detected the expression of ALPK1 in neurons of TGs in wild-type (WT) mice, and it was upregulated after intra-TMJ injection of MIA. Meanwhile, the increased percentage of neurons in TGs expressing ALPK1 and CGRP or ALPK1 and IB4 was also demonstrated by the immunofluorescent double staining. Furthermore, after the MIA injection, ALPK1 mice exhibited attenuated pain behavior, as well as a remarkably decreased percentage of IB4 neurons and an unchanged percentage of CGRP neurons, as compared with WT mice. In vitro assay showed that the value of calcium intensity was weakened in Dil neurons from ALPK1 mice of TMJ pain induced by the MIA injection, in relation to those from WT mice, while it was significantly enhanced with the incubation of recombinant human ALPK1 (rhA). Taken together, these results suggest that ALPK1 promotes mice TMJ pain induced by MIA through upregulation of the sensitization of IB4 neurons in TGs. This study will provide a new potential therapeutic target for the treatment of TMJ pain.
疼痛是颞下颌关节（TMJ）紊乱患者寻求医疗的主要原因之一。然而，由于其机制尚不清楚，目前尚无有效的治疗方法。在这里，我们发现向小鼠 TMJ 注射单碘乙酸（MIA）可早在 3 天内引起典型的关节疼痛，同时三叉神经节（TGs）中降钙素基因相关肽阳性（CGRP）神经元和异硫氰酸荧光素 B4 阳性（IB4）神经元的比例增加。我们之前的研究发现，α-激酶 1（ALPK1）可能参与关节疼痛。在这里，我们检测了野生型（WT）小鼠 TG 神经元中的 ALPK1 表达，发现 MIA 关节内注射后其表达上调。同时，通过免疫荧光双重染色也证实了 TG 中表达 ALPK1 和 CGRP 或 ALPK1 和 IB4 的神经元比例增加。此外，与 WT 小鼠相比，MIA 注射后 ALPK1 小鼠表现出疼痛行为减弱，IB4 神经元比例明显减少，而 CGRP 神经元比例不变。体外实验表明，与 WT 小鼠相比，MIA 诱导的 TMJ 疼痛中 Dil 神经元的钙强度值在 ALPK1 小鼠中减弱，而在用重组人 ALPK1（rhA）孵育后则显著增强。综上所述，这些结果表明，ALPK1 通过上调 TG 中 IB4 神经元的敏化作用促进 MIA 诱导的小鼠 TMJ 疼痛。这项研究将为 TMJ 疼痛的治疗提供一个新的潜在治疗靶点。
