title: A rat knockout model implicates TRPC4 in visceral pain sensation.
abstract: Acute and chronic pain resulting from injury, surgery, or disease afflicts >100 million Americans each year, having a severe impact on mood, mental health, and quality of life. The lack of structural and functional information for most ion channels, many of which play key roles in the detection and transmission of noxious stimuli, means that there remain unidentified therapeutic targets for pain management. This study focuses on the transient receptor potential canonical subfamily 4 (TRPC4) ion channel, which is involved in the tissue-specific and stimulus-dependent regulation of intracellular Ca²⁺ signaling. Rats with a transposon-mediated TRPC4-knockout mutation displayed tolerance to visceral pain induced by colonic mustard oil (MO) exposure, but not somatic or neuropathic pain stimuli. Moreover, wild-type rats treated with a selective TRPC4 antagonist (ML-204) prior to MO exposure mimicked the behavioral responses observed in TRPC4-knockout rats. Significantly, ML-204 inhibited visceral pain-related behavior in a dose-dependent manner without noticeable adverse effects. These data provide evidence that TRPC4 is required for detection and/or transmission of colonic MO visceral pain sensation. In the future, inhibitors of TRPC4 signaling may provide a highly promising path for the development of first-in-class therapeutics for this visceral pain, which may have fewer side effects and less addictive potential than opioid derivatives.
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, KY 40506, United States.
authors.forename: K N
authors.initials: KN
authors.lastname: Westlund
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, KY 40506, United States.
authors.forename: L P
authors.initials: LP
authors.lastname: Zhang
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, KY 40506, United States.
authors.forename: F
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, KY 40506, United States.
authors.forename: R
authors.initials: R
authors.lastname: Nesemeier
authors.affiliation: Department of Biology, University of Kentucky, Lexington, KY 40506, United States; Transposagen Biopharmaceuticals Inc., 535 West Second Street, Lexington, KY 40508, United States.
authors.forename: J C
authors.initials: JC
authors.lastname: Ruiz
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky, Lexington, KY 40506, United States; Department of Pathology, University of Kentucky, Lexington, KY 40506, United States; Transposagen Biopharmaceuticals Inc., 535 West Second Street, Lexington, KY 40508, United States. Electronic address: eostertag@transposagenbio.com.
authors.forename: E M
authors.initials: EM
authors.lastname: Ostertag
authors.affiliation: Transposagen Biopharmaceuticals Inc., 535 West Second Street, Lexington, KY 40508, United States.
authors.forename: J S
authors.initials: JS
authors.lastname: Crawford
authors.affiliation: Cytochem Inc., 6465 Durocher, Suite 400, Montréal, QC H2V 3Z1, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Babinski
authors.affiliation: Cytochem Inc., 6465 Durocher, Suite 400, Montréal, QC H2V 3Z1, Canada.
authors.forename: M M
authors.initials: MM
authors.lastname: Marcinkiewicz
mesh_terms: D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D055786:Gene Knockout Techniques; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D009149:Mustard Plant; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D059226:Nociceptive Pain / Q000188:drug therapy / Q000503:physiopathology; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology; D010938:Plant Oils; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059265:Visceral Pain / Q000188:drug therapy / Q000503:physiopathology*
chemical_list: D000700:Analgesics; D007211:Indoles; C567966:ML 204; D010880:Piperidines; D010938:Plant Oils; D012333:RNA, Messenger; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; C027793:mustard oil
keywords: colon; gastrointestinal tract; gene knockout; morphine alternatives; somatic pain; transposon