Figure 3. Pruritogenic receptors interact synergistically, thereby amplifying itch or pain.

(A) Activation of PAR₂ leads to binding of G proteins (G_αq/11), followed by (B) stimulation of the intracellular PKC pathway and mobilization of intracellular [Ca²⁺] via phopholipase Cβ (PLCβ), diacylglycerol (DAG), and inositol triphosphate (IP₃). PIP₂, phosphatidylinositol 4,5-biphosphate. This results in (C) sensitization of TRPV1 by phosphorylation of the intracellular C terminus (heterologous sensitization). Sensitization of TRPV1 leads to (D) a lowered threshold for capsaicin binding or temperature, i.e., stimulation of TRPV1. This mechanism affects release of neuropeptides (activation of mast cell degranulation) from nerve terminals of sensory nerves as well as stimulation of activation potentials (transmission of pain and pruritus to the spinal cord).