Contribution of TRPA1 as a Downstream Signal of Proteinase-Activated Receptor-2 to Pancreatic Pain

Abstract

Abstract. We examined if TRPA1, like TRPV1, contributes to pancreatic nociceptor excitation following proteinase-activated receptor-2 (PAR2) stimulation and to pancreatitis-related pain in mice. A PAR2-activating peptide, infused into the pancreatic duct, caused spinal Fos expression, which was prevented by AP18, a TRPA1 inhibitor. Repeated administration of cerulein caused referred hyperalgesia accompanying pancreatitis, which was reversed by SB366791, a TRPV1 inhibitor, but not AP18. AP18, administered in combination with a subeffective dose of SB366791, significantly suppressed the referred hyperalgesia. Our findings suggest that TRPA1, like TRPV1, mediates PAR2-triggered pancreatic nociception and that TRPA1 in collaboration with TRPV1 latently contributes to pancreatitis-related pain.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Moreover, the first-generation TRPV1 antagonist, capsazepine, diminished discomfort to colorectal distension in mice (Sugiura et al, 2007), similar to the decrease seen in TRPV1-null animals (Jones et al, 2005a). Interestingly, TRPV1 and TRPA1 antagonists synergistically attenuate caerulein-induced pain behavior and pancreatic inflammation (Schwartz et al, 2011;Terada et al, 2013) and prevent the transition from acute to chronic pain during experimental pancreatitis (Schwartz et al, 2013); after this transition, TRP antagonism is ineffective. Alcohol abuse is a well known cause of acute pancreatitis.…”

“…Both proteins are colocalized in DRG. Stimulation of PAR-2 activates TRPA1 (Dai et al, 2007;Terada et al, 2013). As detailed later, there is evidence that TRPV1 and TRPA1 are not only coexpressed but also functionally coupled in DRG neurons, where they may also form functional heterotetramers.…”

Human Surrogate Models of Histaminergic and Non-histaminergic Itch

“…In the non-histaminergic pathways the key second messenger role is played by transient receptor potential cation channel, subfamily A, member 1 (TRPA1), a downstream target of proteinase-associated receptor 2 (PAR) and Mas-related G-protein coupled receptor member Gsignalling (Mrgpr) (48)(49)(50). TRPA1 appears to be crucial, not only in conveying chronic itch sensation, but also in processes such as neurogenic inflammation, epidermal hyperplasia and altered gene expression in sensory nerves, which frequently accompany chronic itch conditions (48,51).…”

H2S and Pain: A Novel Aspect for Processing of Somatic, Visceral and Neuropathic Pain Signals

“…It has been reported that TRPA1 is sensitized by proteinase-activated receptor-2 (PAR2) activation, contributing to inflammatory pain (Dai et al 2007). We have provided evidence that pharmacological inhibition of TRPA1 prevents the spinal Fos expression following infusion of SLIGRL-NH 2 , a PAR2-activating peptide, into the pancreatic duct, suggesting the pronociceptive role of TRPA1 as a downstream signal of PAR2 activation in the pancreatic nociceptors (Terada et al 2013). Most interestingly, it has been reported that NaHS evokes a time-and concentration-dependent increase in cytosolic calcium concentration in TRPA1-transfected cells (Streng et al 2008) and that NaHS induces calcium influx and inward currents in rat DRG cells, an effect inhibited by a TRPA1 antagonist (Miyamoto et al 2011;Ogawa et al 2012).…”