Abstract
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.
Highlights
Pain is protective, but its dysregulation has a negative impact on an individual's life, as well as a wider socioeconomic impact
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 complete Freund's adjuvant (CFA)-injected side
Alongside endogenous mediators released during inflammation, e.g. protons, we have shown that articular neurons can be activated by the Transient Receptor Potential (TRP) channel agonists capsaicin (TRPV1), cinnamaldehyde (TRPA1) and menthol (TRPM8)
Summary
But its dysregulation has a negative impact on an individual's life, as well as a wider socioeconomic impact Inflammatory joint pain is characteristic of many musculoskeletal disorders, often being more diffuse and longer lasting than cutaneous pain (Lewis, 1938). Numerous animal models of inflammatory joint pain are used experimentally (Gregory et al, 2013) and intra-articular complete Freund's adjuvant (CFA) was chosen for use in this study because it produces robust, unilateral inflammation, alongside behavioral hyperalgesia (Keeble et al, 2005). Spontaneous pain is a hallmark of joint pain, most rodent studies focus on evoked pain behaviors (Arendt-Nielsen, 2017; Schaible et al, 2002). Shifting the emphasis to study natural behaviors during painful conditions and their underlying molecular mechanisms might facilitate the translation of novel analgesics into clinics (Arendt-Nielsen, 2017)
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