Saloman J L, Chung M-K, Ro J Y
University of Maryland Baltimore, School of Dentistry, Department of Neural and Pain Sciences, Program in Neuroscience, 650 W. Baltimore Street, Baltimore, MD 21201, USA.
University of Maryland Baltimore, School of Dentistry, Department of Neural and Pain Sciences, Program in Neuroscience, 650 W. Baltimore Street, Baltimore, MD 21201, USA.
Neuroscience. 2013 Mar 1;232:226-38. doi: 10.1016/j.neuroscience.2012.11.015. Epub 2012 Nov 29.
Musculoskeletal pain conditions, particularly those associated with temporomandibular disorders (TMD) affect a large percentage of the population. Identifying mechanisms underlying hyperalgesia could contribute to the development of new treatment strategies for the management of TMD and other muscle pain conditions. In this study, we provide evidence of functional interactions between two ligand-gated channels, P2X₃ and transient receptor potential V1 (TRPV1), in trigeminal sensory neurons, and propose that the interactions serve as an underlying mechanism for the development of mechanical hyperalgesia. Mechanical sensitivity of the masseter muscle was assessed in lightly anesthetized rats via an electronic anesthesiometer (Ro et al., 2009). Direct intramuscular injection of a selective P2X₃ agonist, alpha,beta-methylene adenosine triphosphate (αβmeATP), induced a dose- and time-dependent hyperalgesia. Mechanical sensitivity in the contralateral muscle was unaffected suggesting local P2X₃ mediate hyperalgesia. Anesthetizing the overlying skin had no effect on αβmeATP-induced hyperalgesia confirming the contribution of P2X₃ from the muscle. Importantly, the αβmeATP-induced hyperalgesia was prevented by pretreatment of the muscle with a TRPV1 antagonist, AMG9810. P2X₃ was co-expressed with TRPV1 in the masseter muscle afferents confirming the possibility for intracellular interactions. Additionally, in a subpopulation of P2Xv/TRPV1 positive neurons, capsaicin-induced Ca(2+) transients were significantly amplified following P2X₃ activation. Finally, activation of P2X₃ induced phosphorylation of serine, but not threonine, residues in TRPV1 in trigeminal ganglia cultures. Significant phosphorylation was observed at 15 min, the time point at which behavioral hyperalgesia was prominent. Previously, activation of either P2X₃ or TRPV1 had been independently implicated in the development of mechanical hyperalgesia. Our data propose P2X₃ and TRPV1 interact in a facilitatory manner, which could contribute to the peripheral sensitization known to underlie masseter hyperalgesia.
肌肉骨骼疼痛病症，尤其是那些与颞下颌关节紊乱症（TMD）相关的病症，影响着很大一部分人群。确定痛觉过敏背后的机制有助于开发新的治疗策略来管理TMD和其他肌肉疼痛病症。在本研究中，我们提供了三叉神经感觉神经元中两个配体门控通道P2X₃和瞬时受体电位香草酸亚型1（TRPV1）之间功能相互作用的证据，并提出这种相互作用是机械性痛觉过敏发展的潜在机制。通过电子麻醉计在轻度麻醉的大鼠中评估咬肌的机械敏感性（Ro等人，2009年）。直接肌肉内注射选择性P2X₃激动剂α,β-亚甲基三磷酸腺苷（αβmeATP）可诱导剂量和时间依赖性痛觉过敏。对侧肌肉的机械敏感性未受影响，表明局部P2X₃介导痛觉过敏。麻醉覆盖的皮肤对αβmeATP诱导的痛觉过敏没有影响，证实了肌肉中P2X₃的作用。重要的是，用TRPV1拮抗剂AMG9810预处理肌肉可预防αβmeATP诱导的痛觉过敏。P2X₃与TRPV1在咬肌传入纤维中共表达，证实了细胞内相互作用的可能性。此外，在P2X₃/TRPV1阳性神经元亚群中，辣椒素诱导的Ca(2+)瞬变在P2X₃激活后显著放大。最后，P2X₃的激活诱导三叉神经节培养物中TRPV1丝氨酸而非苏氨酸残基的磷酸化。在15分钟时观察到显著的磷酸化，此时行为性痛觉过敏最为明显。以前，P2X₃或TRPV1的激活已分别与机械性痛觉过敏的发展有关。我们的数据表明P2X₃和TRPV1以促进性方式相互作用，这可能导致已知为咬肌痛觉过敏基础的外周敏化。
