Pro-inflammatory mediators sensitise transient receptor potential melastatin 3 cation channel (TRPM3) function in mouse sensory neurons.

Abstract

Pro-inflammatory mediators can directly activate pain-sensing neurons, known as nociceptors. Additionally, these mediators can sensitise ion channels and receptors expressed by these cells through transcriptional and post-translational modulation, leading to nociceptor hypersensitivity. A well-characterised group of ion channels that subserve nociceptor sensitisation is the transient receptor potential (TRP) superfamily of cation channels. For example, the roles of TRP channels vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) in nociceptor sensitisation and inflammatory pain have been extensively documented. In the case of TRP melastatin 3 (TRPM3), however, despite the increasing recognition of this channel's role in inflammatory pain, the mediators driving its sensitisation during inflammation remain poorly characterised. Here, using Ca2+ imaging, we found that an inflammatory soup of bradykinin, interleukin 1β (IL-1β) and tumour necrosis factor α (TNFα) sensitised TRPM3 function in isolated mouse sensory neurons; IL-1β and TNFα, but not bradykinin, independently potentiated TRPM3 function. TRPM3 expression and translocation to the membrane remained unchanged upon individual or combined exposure to these inflammatory mediators, which suggests that post-translational modification might occur. Finally, using the complete Freund's adjuvant-induced model of knee inflammation, we found that systemic pharmacological blockade of TRPM3 does not alleviate inflammatory pain (as assessed through evaluation of digging behaviour and dynamic weight bearing), which contrasts with previous reports using different pain models. We propose that the nuances of the immune response may determine the relative contribution of TRPM3 to nociceptive signalling in different neuro-immune contexts. Collectively, our findings improve insight into the role of TRPM3 sensitisation in inflammatory pain.