Figure 2.

Activation and sensitization of nociceptors. (a) Transduction can involve both direct and indirect pathways. The ion channel TRPV1, for example, can be directly opened by increases in temperature or by chemicals released from resident (mast) and recruited (polymorphonuclear leukocyte; PMNL) immune cells, epithelial cells, Schwann cells, fibroblasts and sympathetic post-ganglionic neurons (SPGN). (b) There are multiple points of interaction between second messenger pathways that are engaged after nociceptor activation, including at the levels of signaling molecules such as Ca²⁺, effector molecules such as PKCε, and common targets, such as TRPV1 and NaV1.8 (not shown) for the pathways activated. For clarity, we have omitted positive modulation of TRPV1 by ceramide, p38, PI3K, PKCε and PKA. Also not shown is the translocation of TRPV1 to the cell surface, which may contribute to injury-induced increases in channel activity. (c) Sensitization of nociceptors also involves positive feedback. Activation of ion channels such as TRPV1 results in membrane depolarization and Ca²⁺ influx through TRPV1 and VGCC. Ca²⁺ influx can drive the release of neuropeptides (stored in dense core vesicles; pink) and glutamate (stored in clear vesicles; yellow), both of which can drive further activation of receptors on nociceptors and release mediators from the sources described in a. PGs, prostaglandins; OLAMs, oxidized linoleic acid meabolites; NE, norepinephrine; ER/GPR30, estrogen receptor/G protein receptor-30; 5-HT, serotonin; CaM, calmodulin; PLC, phospholipase C. DAG, diacylglycerol; IP₃, inositol triphosphate; AC, adenylate cyclase; EPAC, cAMP-activated guanine exchange factor; PI3K, phosphoinositide 3-kinase; ERK1/2, extracellular signal–regulated kinases 1 and 2; TNFR, tumor necrosis factor receptor.