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Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice.
Am J Physiol Gastrointest Liver Physiol. 2010 Sep; 299(3):G556-71.AJ

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.

Authors+Show Affiliations

Departments of Surgery, University of California, San Francisco, 94143-0660, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20539005

Citation

Ceppa, Eugene, et al. "Transient Receptor Potential Ion Channels V4 and A1 Contribute to Pancreatitis Pain in Mice." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 299, no. 3, 2010, pp. G556-71.
Ceppa E, Cattaruzza F, Lyo V, et al. Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice. Am J Physiol Gastrointest Liver Physiol. 2010;299(3):G556-71.
Ceppa, E., Cattaruzza, F., Lyo, V., Amadesi, S., Pelayo, J. C., Poole, D. P., Vaksman, N., Liedtke, W., Cohen, D. M., Grady, E. F., Bunnett, N. W., & Kirkwood, K. S. (2010). Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice. American Journal of Physiology. Gastrointestinal and Liver Physiology, 299(3), G556-71. https://doi.org/10.1152/ajpgi.00433.2009
Ceppa E, et al. Transient Receptor Potential Ion Channels V4 and A1 Contribute to Pancreatitis Pain in Mice. Am J Physiol Gastrointest Liver Physiol. 2010;299(3):G556-71. PubMed PMID: 20539005.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice. AU - Ceppa,Eugene, AU - Cattaruzza,Fiore, AU - Lyo,Victoria, AU - Amadesi,Silvia, AU - Pelayo,Juan-Carlos, AU - Poole,Daniel P, AU - Vaksman,Natalya, AU - Liedtke,Wolfgang, AU - Cohen,David M, AU - Grady,Eileen F, AU - Bunnett,Nigel W, AU - Kirkwood,Kimberly S, Y1 - 2010/06/10/ PY - 2010/6/12/entrez PY - 2010/6/12/pubmed PY - 2010/9/25/medline SP - G556 EP - 71 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am J Physiol Gastrointest Liver Physiol VL - 299 IS - 3 N2 - 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. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/20539005/Transient_receptor_potential_ion_channels_V4_and_A1_contribute_to_pancreatitis_pain_in_mice_ L2 - https://journals.physiology.org/doi/10.1152/ajpgi.00433.2009?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -