Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice

Abstract

The mechanisms of pancreatic pain, a cardinal symptom of pancreatitis, are unknown. Proinflammatory agents that activate transient receptor potential (TRP) channels in nociceptive neurons can cause neurogenic inflammation and pain. We report a major role for TRPV4, which detects osmotic pressure and arachidonic acid metabolites, and TRPA1, which responds to 4-hydroxynonenal and cyclopentenone prostaglandins, in pancreatic inflammation and pain in mice. Immunoreactive TRPV4 and TRPA1 were detected in pancreatic nerve fibers and in dorsal root ganglia neurons innervating the pancreas, which were identified by retrograde tracing. Agonists of TRPV4 and TRPA1 increased intracellular Ca(2+) concentration ([Ca(2+)](i)) in these neurons in culture, and neurons also responded to the TRPV1 agonist capsaicin and are thus nociceptors. Intraductal injection of TRPV4 and TRPA1 agonists increased c-Fos expression in spinal neurons, indicative of nociceptor activation, and intraductal TRPA1 agonists also caused pancreatic inflammation. The effects of TRPV4 and TRPA1 agonists on [Ca(2+)](i), pain and inflammation were markedly diminished or abolished in trpv4 and trpa1 knockout mice. The secretagogue cerulein induced pancreatitis, c-Fos expression in spinal neurons, and pain behavior in wild-type mice. Deletion of trpv4 or trpa1 suppressed c-Fos expression and pain behavior, and deletion of trpa1 attenuated pancreatitis. Thus TRPV4 and TRPA1 contribute to pancreatic pain, and TRPA1 also mediates pancreatic inflammation. Our results provide new information about the contributions of TRPV4 and TRPA1 to inflammatory pain and suggest that channel antagonists are an effective therapy for pancreatitis, when multiple proinflammatory agents are generated that can activate and sensitize these channels.

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…Consistent with these studies, capsaicin-treated animals are less susceptible to pancreatitis and treatment with the TRPV1 antagonist capsazepine or resiniferatoxin-induced denervation protects against caerulein-induced pancreatitis (Nathan et al, 2001;Noble et al, 2006). TRPA1-positive afferent nerve fibers innervate the pancreas and respond to the TRPA1 activators allyl isothiocyanate and endogenous agonists produced in pancreatic inflammation (15dPGJ2 and 4-HNE), and responses are attenuated by TRPA1 inhibitors or in trpa1 2/2 mice (Ceppa et al, 2010;Schwartz et al, 2011Schwartz et al, , 2013. The administration of TRPV1 and TRPA1 agonists into the pancreatic duct induces c-fos expression and NK 1 R internalization in spinal cord and causes nocifensive behavior, which together suggest activation of pain pathways.…”

“…The involvement of TRPA1, TRPV1, and TRPV4 in pancreatitis and pancreatic pain has been investigated, and observations support a role for TRPV1 and TRPA1 in neurogenic inflammation of the pancreas. TRPV4-positive nerve fibers innervate the pancreas, and pancreatic DRG afferents express functional TRPV4, although no functional changes in TRPV4 have been associated with acute pancreatic inflammation (Ceppa et al, 2010). Nerve fibers positive for both TRPV1 and CGRP are also in close association with pancreatic acinar cells and predominantly originate from spinal afferent DRG neurons (Fasanella et al, 2008).…”

The role of thermosensitive TRP (transient receptor potential) channels in insulin secretion [Review]

“…TRPV1 expressed in sensory neurons was found to be involved in β-cell stress and islet inflammation through control of neuropeptide release levels as described above. There are reports indicating that TRPA1-and TRPV4-expressing sensory neurons are involved in pancreatitis-related pain sensation [48,49], suggesting that not only TRPV1 but also other thermosensitive TRP channels expressed in sensory neurons (TRPV2, TRPM8, TRPA1 and possibly TRPV4) could also be involved in pancreatic β-cell functions. TRPM3 has recently been found to be sensitive to noxious heat [50], although it is not clear whether TRPM3 can also be classified as a thermosensitive TRP channel.…”

The role of TRPA1 in visceral inflammation and pain

“…52 The expression of TRPA1 has also been demonstrated in DRG neurons innervating the pancreas, and is believed to participate in inflammation and pain related to acute pancreatitis in mice. 53,54 TRPA1 agonists have been shown to induce pancreatic inflammation and hyperexcitability of spinal nociceptors. 53 Furthermore, cerulein-evoked pancreatic inflammation induced a significant increase in the expression and activation of both TRPA1 and TRPV1, as well as overall excitability of pancreatic sensory neurons.…”

“…53,54 TRPA1 agonists have been shown to induce pancreatic inflammation and hyperexcitability of spinal nociceptors. 53 Furthermore, cerulein-evoked pancreatic inflammation induced a significant increase in the expression and activation of both TRPA1 and TRPV1, as well as overall excitability of pancreatic sensory neurons. 54 Interestingly, while the inhibition of both TRPA1 and TRPV1 individually reduced the severity of pancreatitis, the combined treatment appeared to be more effective.…”