Inflammatory pain: the cellular basis of heat hyperalgesia

Abstract

Injury or inflammation release a range of inflammatory mediators that increase the sensitivity of sensory neurons to noxious thermal or mechanical stimuli. The heat- and capsaicin-gated channel TRPV1, which is an important detector of multiple noxious stimuli, plays a critical role in the development of thermal hyperalgesia induced by a wide range of inflammatory mediators. We review here recent findings on the molecular mechanisms of sensitisation of TRPV1 by inflammatory mediators, including bradykinin, ATP, NGF and prostaglandins. We describe the signalling pathways believed to be involved in the potentiation of TRPV1, and our current understanding of how inflammatory mediators couple to these pathways.

Keywords: Pain; TRPV1; capsaicin; heat; inflammation; intracellular signalling; protein kinase; sensory transduction.

Fig. (1)

Sites on TRPV1 modulating function. The hypothesised 6-transmembrane domain structure of TRPV1 is shown, with a pore loop between TM5 and TM6. A functional homomeric channel is formed from four such subunits. Sites at which phosphorylation is known to modulate TRPV1 function are shown together with the kinases responsible. Protons can bind to two extracellular glutamates, and protonation of E600 has an apparently similar effect on TRPV1 gating to phosphorylation at S502. Ankyrin domains, the capsaicin-binding domain and the hypothesised C-terminal PIP₂ binding domain are also shown.

Fig. (2)

Inflammatory mediators and intracellular signalling pathways modulating TRPV1. NGF and other mediators activating tyrosine kinase-coupled receptors promote the insertion of TRPV1 into the membrane, from a pool located in subcellular vesicles, via a pathway in which PI3K plays an early role while the downstream tyrosine kinase Src activates trafficking to the membrane by phosphorylating Y199 in the N-terminal tail of TRPV1. These receptors also couple to a lesser extent to TRPV1 via PLCγ and PKCε. Seven-transmembrane G-protein coupled receptors activated by a range of inflammatory mediators, including bradykinin and ATP, activate PLCβ and consequently PKCε, which enhances the activity of TRPV1 in the surface membrane by phosphorylating S502 and S800. Prostaglandins PGE₂ and PGI₂ activate EP and IP receptors, which couple to PKA and PKCε. Glutamate (and probably other agonists such as bradykinin) appears to act at least in part via an indirect route in which the production of arachidonic acid (AA) leads to the synthesis of prostaglandins via the cyclo-oxygenase (COX) pathway and activation of prostaglandin receptors.