Pro-inflammatory mediators sensitise Transient Receptor Potential Melastatin 3 cation channel (TRPM3) signalling in mouse sensory neurons

Abstract

Pro-inflammatory mediators can directly activate pain-sensing neurons, known as nociceptors. Additionally, these mediators can potentiate or 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 channels role in inflammatory pain, the mechanisms driving its sensitisation during inflammation remain poorly understood. Here, we found that an inflammatory soup of bradykinin, interleukin 1{beta} (IL-1{beta}) and tumour necrosis factor (TNF) sensitised TRPM3 function in isolated mouse sensory neurons; IL-1{beta} and TNF, 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 post-translational modification occurs. Finally, using the model of complete Freunds adjuvant-induced knee inflammation, we found that pharmacological blockade of TRPM3 does not alleviate inflammatory pain, 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/612393v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@11e90acorg.highwire.dtl.DTLVardef@1ac1c2aorg.highwire.dtl.DTLVardef@6d116forg.highwire.dtl.DTLVardef@93c605_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG