Acute inflammation sensitizes knee-innervating sensory neurons and decreases mouse digging behavior in a TRPV1-dependent manner.
Acute inflammation sensitizes knee-innervating sensory neurons and decreases mouse digging behavior in a TRPV1-dependent manner.
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DOI：
10.1016/j.neuropharm.2018.09.014
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发表时间：
2018-12
影响因子：
4.7
通讯作者：
Smith ESJ
中科院分区：
文献类型：
--
作者：
Chakrabarti S;Pattison LA;Singhal K;Hockley JRF;Callejo G;Smith ESJ
持续性、自发性疼痛是炎症性关节疼痛的特征，降低了个人的生活质量。为了了解炎性关节疼痛的神经基础，我们在小鼠一侧膝关节注射完全弗氏佐剂(CFA)，这减少了它们的自然挖掘行为。我们假设，膝关节神经支配的背根节(DRG)神经元的敏化是这种改变行为的基础。为了验证这一假设，我们对逆行标记的膝关节神经原代背根神经节神经元培养进行了电生理记录，并测量了它们对一些电和化学刺激的反应。我们发现，在CFA诱导的膝关节炎症后24小时，膝关节神经元的动作电位产生阈值降低，GABA和辣椒素敏感性增加，但对酸的敏感性没有改变。炎症诱导的膝神经细胞敏化在培养24小时内持续存在，但在培养48小时后观察不到。通过免疫组织化学方法，我们发现注射CFA的膝关节神经细胞辣椒素敏感性的增加与辣椒素受体--瞬时受体香草素1(TRPV1)的表达增强有关。我们还观察到TRPV1与神经生长因子(NGF)的受体原肌球蛋白受体激酶A(TrkA)共表达的增加，表明NGF部分诱导了TRPV1的表达增加。最后，我们发现全身性给予TRPV1拮抗剂A-425619能逆转CFA引起的挖掘行为的下降，进一步证实了膝部神经元表达的TRPV1在急性炎症性关节疼痛中的作用。膝部炎症使小鼠挖洞行为减少。支配膝关节的背根神经节神经元在炎症后高度兴奋。在膝关节神经支配的神经元中观察到NGF介导的TRPV1表达的增加。全身应用TRPV1拮抗剂可使小鼠的挖掘行为正常化。
Ongoing, spontaneous pain is characteristic of inflammatory joint pain and reduces an individual's quality of life. To understand the neural basis of inflammatory joint pain, we made a unilateral knee injection of complete Freund's adjuvant (CFA) in mice, which reduced their natural digging behavior. We hypothesized that sensitization of knee-innervating dorsal root ganglion (DRG) neurons underlies this altered behavior. To test this hypothesis, we performed electrophysiological recordings on retrograde labeled knee-innervating primary DRG neuron cultures and measured their responses to a number of electrical and chemical stimuli. We found that 24-h after CFA-induced knee inflammation, knee neurons show a decreased action potential generation threshold, as well as increased GABA and capsaicin sensitivity, but have unaltered acid sensitivity. The inflammation-induced sensitization of knee neurons persisted for 24-h in culture, but was not observed after 48-h in culture. Through immunohistochemistry, we showed that the increased knee neuron capsaicin sensitivity correlated with enhanced expression of the capsaicin receptor, transient receptor potential vanilloid 1 (TRPV1) in knee-innervating neurons of the CFA-injected side. We also observed an increase in the co-expression of TRPV1 with tropomyosin receptor kinase A (TrkA), which is the receptor for nerve growth factor (NGF), suggesting that NGF partially induces the increased TRPV1 expression. Lastly, we found that systemic administration of the TRPV1 antagonist, A-425619, reversed the decrease in digging behavior induced by CFA injection, further confirming the role of TRPV1, expressed by knee neurons, in acute inflammatory joint pain. Knee inflammation decreases digging behavior in mice. Knee-innervating dorsal root ganglion neurons are hyperexcitable after inflammation. NGF-mediated increase in TRPV1 expression is observed in knee-innervating neurons. Systemic TRPV1 antagonist administration normalises digging behavior in mice.
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影响因子：
16.6
作者：
Chen, Jeremy Tsung-chieh;Guo, Da;Campanelli, Dario;Frattini, Flavia;Mayer, Florian;Zhou, Luming;Kuner, Rohini;Heppenstall, Paul A.;Knipper, Marlies;Hu, Jing
通讯作者：
Hu, Jing
影响因子：
13.3
作者：
Garrison, Sheldon R.;Stucky, Cheryl L.
通讯作者：
Stucky, Cheryl L.
影响因子：
7
作者：
Chen Y;Willcockson HH;Valtschanoff JG
通讯作者：
Valtschanoff JG
影响因子：
2.5
作者：
Flake, NM;Gold, MS
通讯作者：
Gold, MS
影响因子：
3.6
作者：
Cervero, F;Laird, JMA;García-Nicas, E
通讯作者：
García-Nicas, E