*2.2. TRPV1*

Among TRP channels expressed in primary sensory neurons, TRPV1 is well-known for its role in pain [3]. TRPV1 is mainly expressed in small DRG and TG neurons and is activated by capsaicin, capsiate, camphor, allicin, 2-aminoethoxydiphenyl borate, anandamide, N-arachidonoyl dopamine, resiniferatoxin, nitrogen oxide, low pH, noxious heat, hypertonicity, and the double-knot toxin in tarantula venom [14,72–81]. Expression levels of TRPV1 are enhanced by NGF receptor activation in DRG neurons, while TRPV1 is transported to peripheral termini [82]. TRPV1 activation is enhanced upon phosphorylation by PKA and PKC via A-kinase anchor protein in DRG neurons activated by GPCRs [83–86]. Due to the lowered thermal threshold of phosphorylated TRPV1 at body temperature, allodynia can be caused by inflammatory pathways depending on GqPCR activation. Many inflammatory factors, including prostaglandin E2, adenosine, ATP, bradykinin, protease, and NGF, are released following tissue injury, with protein kinases activated downstream of each GPCR [1]. In addition, the ionotropic ATP receptor, P2X, may also be involved in modulating activity of protein kinases that target TRP channels, as evidenced by activation of cytosolic PLA2 by P2X3 and P2X2/3 receptors during neuropathic pain [39]. Activated PLA2 can in turn activate PKC to promote phosphorylation of TRP [40]. Taken together, these findings suggest that TRP channel phosphorylation may be caused by both P2X and metabotropic P2Y receptor activation in primary sensory neurons.
