Proteinase-Activated Receptor 2-Mediated Potentiation of Transient Receptor Potential Vanilloid Subfamily 1 Activity Reveals a Mechanism for Proteinase-Induced Inflammatory Pain

Abstract

Proteinase-activated receptor (PAR) 2 is expressed on a subset of primary afferent neurons and involved in inflammatory nociception. Transient receptor potential vanilloid subfamily 1 (TRPV1) is a sensory neuron-specific cation channel that responds to capsaicin, protons, or heat stimulus. Here, we show that TRPV1 is coexpressed with PAR2 but not with PAR1 or PAR3, and that TRPV1 can functionally interact with PAR2. In human embryonic kidney 293 cells expressing TRPV1 and PAR2, PAR2 agonists increased capsaicinor proton-evoked TRPV1 currents through a PKC-dependent pathway. After application of PAR2 agonists, temperature threshold for TRPV1 activation was reduced from 42°C to well below the body temperature. PAR2-mediated Fos expression in spinal cord was decreased in TRPV1-deficient mice. The functional interaction was also observed in mouse DRG neurons and proved at a behavioral level. These represent a novel mechanism through which trypsin or tryptase released in response to tissue inflammation might trigger the sensation of pain by PAR2 activation.

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

“…In HEK cells and DRG neurons, PAR 2 and TRPV1 are functionally coupled, application of PAR 2 specific agonists, trypsin or tryptase potentiated capsaicininduced currents [60,64]. Dai and colleagues confirmed a functional interaction between TRPV1 and PAR 2 in HEK293 and in mouse DRG neurons by a patch-clamp technique [61]. Further, Amadesi et al have shown that PAR 2 agonists in sensory neurons promoted translocation of the epsilon form of PKC and protein kinase A catalytic subunits from the cytosol, to the plasma membrane [64].…”

“…TRPV1 is a nonselective cation channel that is activated by protons, elevated temperature, and certain lipids, as well as by exogenous vanilloid molecules such as capsaicin [58,59]. For instance, PAR 2 is co-expressed with TRPV1, in sensory neurons of dorsal root ganglia [60,61] on nerve fibers of the bladder [15] or of pancreas [12]. On the nerve fibers arising from the pancreas, PAR 2 and TRPV1 are also functionally coupled, since activation of PAR 2 sensitized DRG neurons responses to capsaicin, as measured by an enhancement of capsaicin-evoked CGRP release [12].…”

Impaired Nociception and Inflammatory Pain Sensation in Mice Lacking the Prokineticin Receptor PKR1: Focus on Interaction between PKR1 and the Capsaicin Receptor TRPV1 in Pain Behavior

“…Additionally, the development of Bv8-, bradykinin-, and prostaglandin E2 (PGE2)-induced nociceptor sensitization as well as hyperalgesia to acute and chronic inflammatory stimuli were investigated in PKR1 knock-out (KO) mice. Considering that PKR1 is a G-protein-coupled metabotropic receptor (Lin et al, 2002) and that similar signaling receptors such as ATP, bradykinin, and proteinase-activated and chemokine receptors sensitize the vanilloid receptor TRPV1 to noxious stimuli (Tominaga et al, 2001;Sugiura et al, 2002;Dai et al, 2004;Zhang et al, 2005), we examined whether a positive co-operativity between the PKR1 prokineticin receptor and the TRPV1 channel contributes to acute nociception and pain behavior.…”

Antipain Y, a new antipain analog that inhibits neurotransmitter release from rat dorsal root ganglion neurons

“…5 PAR2 also sensitizes sensory neurons by the transient receptor potential vanilloid 1 (TRPV1)-protein kinase C pathway. 18 Although we have not examined whether antipain Y inhibits the signaling pathway underlying sensitization mediated by TRPV1, it is likely that antipain Y and its related inhibitors are potential therapeutic compounds for sensory neuron-related disorders by inhibition of PAR activation.…”