Activation of protease‐activated receptor‐4 inhibits the intrinsic excitability of colonic dorsal root ganglia neurons

Abstract

The antinociceptive mechanism underlying protease-activated receptor-4 (PAR(4)) activation was studied in Fast Blue-labelled dorsal root ganglia (DRG) neurons from mouse colon which expressed transcript for PAR(4). Whole cell perforated patch clamp recordings were obtained from these neurons and the effects on neuronal excitability of PAR(4) activating peptides (AP) and reverse peptides (RP) were examined. A 3-min application of PAR(4)-AP (100 micromol L(-1)) markedly suppressed the number of action potential discharged at twice rheobase for up to 60 min. PAR(4)-RP had no effect. PAR(4) application suppresses the excitatory effects of PAR(2). These findings demonstrated that activation of PAR(4) on colonic DRG neurons suppresses their excitability, suggesting these receptors could provide important targets for modifying pain in colonic GI disorders such as IBS and IBD.

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

“…However, in contrast to PAR 1 , PAR 4 was functional on DRG neurons, wherein its activation was able to reduce capsaicin, PAR 2 -AP, TRPV4 agonist or KClinduced calcium mobilization [30,31]. Study of neuronal currents following PAR 4 agonist peptide treatment provides a direct support for the concept of a direct effect on neurons and unequivocal evidence that suppression of intrinsic excitability can contribute to the observed antinociceptive effect of PAR 4 [32]. At the colonic level, PAR 4 agonists modulate colonic nociceptive response, inhibit colonic hypersensitivity and primary afferent activation to pronociceptive mediators [31].…”

The Expression of Protease-Activated Receptor 2 and 4 in the Colon of Irritable Bowel Syndrome Patients

“…In addition, PAR4 activation significantly increases the nociceptive threshold in response to noxious stimuli and that selective activation of this receptor significantly reduces the carrageenan-induced inflammatory hyperalgesia and allodynia [13]. Other studies have shown that the activation of PAR4 on colonic dorsal root ganglion neurons suppresses their excitability and suppresses the pro-nociceptive actions of PAR2 [25]. In addition to somatic or visceral sensitivity, PAR4 activation contributes to the relaxation of smooth muscle in the esophagus [26].…”

New insights into protease-activated receptor 4 signaling pathways in the pathogenesis of inflammation and neuropathic pain: a literature review

“…46 Additionally, it is clear that PAR4 receptors are expressed in a population of peptide-expressing, IB4-negative nociceptive sensory neurons, where they couple to PKCe, causing sensitization of TRPV1 and promoting the heat-dependent release of the pro-inflammatory neuropeptide CGRP. These observations suggest a role for PAR4 receptors in promoting inflammation and pain following the release of thrombin; 30,33,49,50 however, evidence in the model of inflammation showed that the administration of a PAR4 activator peptide (PAR4-AP) caused the formation of edema neutrophils recruitment, PAR4-mediated edema is dependent on the recruitment of neutrophils and components of the kallikreinkinin system. 18,19 Specific Signaling Pathways of PAR4 in Neurons PAR4-dependent ERK/MAPK activation Mitogen-activated protein kinases (MAPKs) are a family of evolutionally conserved molecules that are essential in cell signaling and gene expression.…”