Inflammatory mediators modulating the transient receptor potential vanilloid 1 receptor: therapeutic targets to treat inflammatory and neuropathic pain

The transient receptor potential vanilloid 1 receptor (TRPV1) plays an important role in inflammatory heat hyperalgesia. TRPV1 is a non-selective cation channel gated by noxious heat, protons and capsaicin, thus being regarded as a polymodal molecular integrator in nociception. Abundant evidence has demonstrated that TRPV1 is also modulated by numerous inflammatory mediators, including growth factors, neurotransmitters, peptides or small proteins, lipids, chemokines and cytokines. By activating multiple protein kinases to increase the phosphorylation of TRPV1, pronociceptive inflammatory mediators sensitise the TRPV1 response to noxious heat, protons and capsaicin, thus augmenting thermal hyperalgesia. In contrast, by inhibiting protein kinases or other mechanisms, antinociceptive inflammatory mediators suppress the response of TRPV1 to these stimuli, thus damping thermal hyperalgesia. The positive modulation of TRPV1 by inflammatory mediators may constitute a novel mechanism underlying sustained inflammatory or neuropathic pain. Blocking pronociceptive inflammatory mediator-exerted sensitising effects or boosting antinociceptive inflammatory mediator-induced suppressing effects on TRPV1 should be considered as sources of novel potential therapies to more effectively treat chronic pain conditions.