Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice.
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.
Departments of Surgery, University of California, San Francisco, 94143-0660, USA.
Eugene
E
Ceppa
Fiore
F
Cattaruzza
Victoria
V
Lyo
Silvia
S
Amadesi
Juan-Carlos
JC
Pelayo
Daniel P
DP
Poole
Natalya
N
Vaksman
Wolfgang
W
Liedtke
David M
DM
Cohen
Eileen F
EF
Grady
Nigel W
NW
Bunnett
Kimberly S
KS
Kirkwood
D000447:Aldehydes / Q000633:toxicity; D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity; D005260:Female; D005727:Ganglia, Spinal / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007509:Irritants / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009149:Mustard Plant / Q000633:toxicity; D009619:Nociceptors / Q000502:physiology; D010146:Pain / Q000209:etiology / Q000378:metabolism*; D010179:Pancreas / Q000187:drug effects / Q000294:innervation / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D010938:Plant Oils / Q000633:toxicity; D013116:Spinal Cord / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D007509:Irritants; D010938:Plant Oils; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C486576:Trpv4 protein, mouse; C027576:4-hydroxy-2-nonenal; C027793:mustard oil