TRPC5 as a modulator of TRPV1 signalling in pathological pain states.

Neuropathic pain is a major health problem and occurs after lesions and damage of the somatosensory nervous system. Clinically it remains poorly treatable despite extensive research efforts. Members of the transient receptor potential (TRP) superfamily, including TRPC5 and TRPV1, are key regulators of sensory perception and neuronal excitability. While TRPV1 is well known for its role in physiological and pathophysiological nociception, TRPC5 has been recently identified as a potential target in different pathological pain conditions. Here, we investigated the interaction between TRPC5 and TRPV1 in dorsal root ganglia (DRG) peripheral neurons from mice and in heterologous expression systems. Performing qPCR, we observed significantly upregulated TRPC5 mRNA expression in dorsal root ganglia following induction of oxaliplatin-induced peripheral neuropathic pain (OIPN), but not in inflammatory or diabetic neuropathic pain models. Calcium imaging experiments showed that that Lysophosphatidylcholines (LPCs) and Hydroxyeicosatetraenoicacids (HETEs) act as endogenous TRPC5 modulators. Pharmacological inhibition of TRPC5 by HC070 reduced TRPV1 mediated calcium responses in transfected HEK293 cells and primary sensory neurons from DRGs without effecting TRPM8-or TRPA1-induced calcium responses. Moreover, HC070 prevented protein kinase C (PKC)- and A (PKA)-dependent sensitization of TRPV1 induced by bradykinin and 8-Bromo-cAMP. Finally, FLIM-FRET experiments confirmed a close physical interaction between TRPC5 and TRPV1. Overall, our findings suggest TRPC5 as a modulatory partner of TRPV1 and highlight its role in nociceptive signalling under pathological circumstances. Because of this TRPC5 inhibition may be an indirect and promising strategy for reducing TRPV1 exacerbated activity in pathological pain states.