Abstract
Genetic ablation or pharmacological inhibition of the heat-activated cation channel TRPM3 alleviates inflammatory heat hyperalgesia, but the underlying mechanisms are unknown. We induced unilateral inflammation of the hind paw in mice, and directly compared expression and function of TRPM3 and two other heat-activated TRP channels (TRPV1 and TRPA1) in sensory neurons innervating the ipsilateral and contralateral paw. We detected increased Trpm3 mRNA levels in dorsal root ganglion neurons innervating the inflamed paw, and augmented TRP channel-mediated calcium responses, both in the cell bodies and the intact peripheral endings of nociceptors. In particular, inflammation provoked a pronounced increase in nociceptors with functional co-expression of TRPM3, TRPV1 and TRPA1. Finally, pharmacological inhibition of TRPM3 dampened TRPV1- and TRPA1-mediated responses in nociceptors innervating the inflamed paw, but not in those innervating healthy tissue. These insights into the mechanisms underlying inflammatory heat hypersensitivity provide a rationale for developing TRPM3 antagonists to treat pathological pain.
Highlights
Painful stimuli are detected by nociceptors in peripheral tissues and are transmitted as action potentials towards the central nervous system to elicit pain sensation (Viana et al, 2019; von Hehn et al, 2012; Vriens et al, 2014)
We addressed whether tissue inflammation is associated with increased expression of mRNA encoding TRPM3, TRPA1, and TRPV1, in particular in sensory neurons that innervate the inflamed tissue
The fraction of TRPA1- or TRPV1-positive dorsal root ganglion (DRG) neurons did not differ significantly between WGA-AF647+ and WGA-AF647-DRG neurons on the ipsilateral and contralateral sides (Figure 1E,G). These results suggest that inflammation is associated with an increased transcription of TRPM3, in sensory neurons innervating the inflamed tissue, whereas no inflammation-related changes were found in the mRNA levels of TRPV1 and TRPA1
Summary
Painful stimuli are detected by nociceptors in peripheral tissues and are transmitted as action potentials towards the central nervous system to elicit pain sensation (Viana et al, 2019; von Hehn et al, 2012; Vriens et al, 2014). The search for new analgesic drugs with novel mechanisms of action inevitably depends on a deep understanding of the cellular and molecular mechanisms underlying nociceptor sensitization (Colloca et al, 2017) In this context, several members of the transient receptor potential (TRP) superfamily of cation channels play key roles as primary molecular sensors in nociceptor neurons, directly involved in translating external stimuli into neuronal activity and pain (Basbaum et al, 2009). The precise mechanisms and the relative contributions of the heat-activated TRP channels to nociceptor sensitization under inflammatory conditions remain incompletely understood To address this problem, we induced experimental inflammation in one hindpaw of mice and evaluated changes in expression and function of TRPM3, TRPA1, and TRPV1 in sensory neurons. These findings elucidate a prominent role of TRPM3 in inflammatory hyperalgesia, and provide a rationale for the development of TRPM3 antagonists to treat inflammatory pain
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