Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, Chicago, IL, USA.
Department of Biomolecular Medicine, Center for Medical Genetics, Ghent University, Ghent, Belgium.
Mol Pain. 2024 Jan-Dec;20:17448069241258106. doi: 10.1177/17448069241258106.
Transient Receptor Potential Vanilloid 1 (TRPV1) is a nonselective cation channel expressed by pain-sensing neurons and has been an attractive target for the development of drugs to treat pain. Recently, Src homology region two domain-containing phosphatase-1 (SHP-1, encoded by ) was shown to dephosphorylate TRPV1 in dorsal root ganglia (DRG) neurons, which was linked with alleviating different pain phenotypes. These previous studies were performed in male rodents only and did not directly investigate the role of SHP-1 in TRPV-1 mediated sensitization. Therefore, our goal was to determine the impact of overexpression on TRPV1-mediated neuronal responses and capsaicin-induced pain behavior in mice of both sexes. Twelve-week-old male and female mice overexpressing (Shp1-Tg) and their wild type (WT) littermates were used. overexpression was confirmed in the DRG of Shp1-Tg mice by RNA in situ hybridization and RT-qPCR. and were found to be co-expressed in DRG sensory neurons in both genotypes. Functionally, this overexpression resulted in lower magnitude intracellular calcium responses to 200 nM capsaicin stimulation in DRG cultures from Shp1-Tg mice compared to WTs. , we tested the effects of overexpression on capsaicin-induced pain through a model of capsaicin footpad injection. While capsaicin injection evoked nocifensive behavior (paw licking) and paw swelling in both genotypes and sexes, only WT mice developed mechanical allodynia after capsaicin injection. We observed similar level of TRPV1 protein expression in the DRG of both genotypes, however, a higher amount of tyrosine phosphorylated TRPV1 was detected in WT DRG. These experiments suggest that, while SHP-1 does not mediate the acute swelling and nocifensive behavior induced by capsaicin, it does mediate a protective effect against capsaicin-induced mechanical allodynia in both sexes. The protective effect of SHP-1 might be mediated by TRPV1 dephosphorylation in capsaicin-sensitive sensory neurons of the DRG.
瞬时受体电位香草酸 1 型（TRPV1）是一种痛觉神经元表达的非选择性阳离子通道，一直是开发治疗疼痛药物的有吸引力的靶点。最近，Src 同源性 2 结构域磷酸酶-1（SHP-1，由 编码）被证明可使背根神经节（DRG）神经元中的 TRPV1 去磷酸化，这与缓解不同的疼痛表型有关。这些先前的研究仅在雄性啮齿动物中进行，并未直接研究 SHP-1 在 TRPV-1 介导的敏化中的作用。因此，我们的目标是确定在雄性和雌性小鼠中过表达 对 TRPV1 介导的神经元反应和辣椒素诱导的疼痛行为的影响。使用了 12 周龄的过表达 （Shp1-Tg）和它们的野生型（WT）同窝仔鼠。通过 RNA 原位杂交和 RT-qPCR 证实了 Shp1-Tg 小鼠 DRG 中的 过表达。在两种基因型的 DRG 感觉神经元中均发现 与 共表达。功能上，与 WT 相比，Shp1-Tg 小鼠 DRG 培养物对 200 nM 辣椒素刺激的细胞内钙反应幅度较小。为了测试 过表达对辣椒素诱导的疼痛的影响，我们通过辣椒素足底注射模型进行了测试。虽然辣椒素注射在两种基因型和性别中均引起伤害性行为（舔足）和足肿胀，但只有 WT 小鼠在辣椒素注射后出现机械性痛觉过敏。我们观察到两种基因型的 DRG 中 TRPV1 蛋白表达水平相似，但 WT DRG 中检测到更多的酪氨酸磷酸化 TRPV1。这些实验表明，虽然 SHP-1 不介导辣椒素诱导的急性肿胀和伤害性行为，但它确实介导了两性对辣椒素诱导的机械性痛觉过敏的保护作用。SHP-1 的保护作用可能是通过 DRG 中辣椒素敏感感觉神经元中的 TRPV1 去磷酸化介导的。
