The role of heat-activated TRP channels in pain and inflammation

Acute pain is unpleasant but physiologically relevant. When pain is triggered to protect us from a potentially dangerous situation, the benefits of pain outweigh the drawbacks. Chronic pain has, in contrast to acute pain, lost its protective function and persists long after the initial cause. Despite intensive research, the underlying molecular and cellular basis of chronic pain remains poorly understood. The search for new analgesic drugs with novel mechanisms of action inevitably depends on a better and deeper understanding of nociceptor functioning. In this thesis, we investigated the role of heat-activated transient receptor potential (TRP) ion channels and in particular the melastatin ion channel, type 3 (TRPM3). TRPM3 is a Ca2+-permeable molecular sensor expressed in nociceptor neurons and is activated by a wide range of thermal and chemical stimuli.We found that TRPM3 and two other heat-activated TRP channels (TRPV1 and TRPA1) form an essential TRP trio that detects painfully hot temperatures. Acute heat detection is maintained as long as one of the three TRP sensors is present. Next, we investigated the molecular mechanisms that underly the development of neuronal hypersensitivity (i.e. hyperalgesia). A new optical imaging technique was developed to measure TRP-dependent responses in the dorsal root ganglia (DRG) and sensory nerve endings of the skin. We found that hyperalgesia is associated with an upregulation of Trpm3 mRNA and with increased TRPM3-mediated responses. Intriguingly, we found that TRPM3 is required for the inflammatory-induced increased activity of TRPV1 and TRPA1.Taken together, this thesis produces valuable novel insights into the mechanisms of heat-activated TRP channels in acute heat sensing and inflammatory pain and stimulate further research towards novel TRPM3-related pain therapies.

Publication year:2021

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