Acute inflammation sensitizes knee-innervating sensory neurons and decreases mouse digging behavior in a TRPV1-dependent manner.
Pattison, Luke A
Hockley, James RF
Smith, Ewan St John
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Chakrabarti, S., Pattison, L. A., Singhal, K., Hockley, J. R., Callejo, G., & Smith, E. S. J. (2018). Acute inflammation sensitizes knee-innervating sensory neurons and decreases mouse digging behavior in a TRPV1-dependent manner.. Neuropharmacology, 143 49-62. https://doi.org/10.1016/j.neuropharm.2018.09.014
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.
Digging behavior, Dorsal root ganglion neurons, Inflammation, Joint pain, Sensitization, TRPV1, Animals, Anti-Inflammatory Agents, Non-Steroidal, Arthralgia, Capsaicin, Cells, Cultured, Disease Models, Animal, Female, Freund's Adjuvant, Ganglia, Spinal, Hindlimb, Inflammation, Isoquinolines, Mice, Inbred C57BL, Motor Activity, Receptor, trkA, Sensory Receptor Cells, TRPV Cation Channels, Urea, gamma-Aminobutyric Acid
S.C. was supported by a Gates Cambridge Trust scholarship and L.A.P. was supported by the University of Cambridge BBSRC Doctoral Training Programme (BB/M011194/1).
ARTHRITIS RESEARCH UK (20930)
Rosetrees Trust (A1296)
Biotechnology and Biological Sciences Research Council (BB/M011194/1)
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External DOI: https://doi.org/10.1016/j.neuropharm.2018.09.014
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285399
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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