Proteinases and proteinase-activated receptor 2: a possible role to promote visceral hyperalgesia in rats.
OBJECTIVE
PAR-2s are highly expressed throughout the gastrointestinal tract. These receptors are cleaved by trypsin and mast cell tryptase and can be activated by peptides corresponding to the tethered ligand of the receptor (SLIGRL-NH2 for rat). The aim of this study was to determine whether colonic administration of PAR-2 agonists affects visceral sensitivity to rectal distention in conscious rats.


METHODS
Abdominal contractions (a criteria of visceral pain) were recorded in rats equipped with intramuscular electrodes. Rectal distention was performed at various times after intracolonic infusion of SLIGRL-NH2 and trypsin. Inflammation parameters and permeability were followed in the colon after the intracolonic injections. Fos expression at a spinal level (L4-L6) was also studied 2 hours after intracolonic injection of SLIGRL-NH2.


RESULTS
Rectal distention significantly increased abdominal contractions starting at the RD volume of 0.8 mL. Intracolonic injection of SLIGRL-NH2 (200 microg/rat) and trypsin (200 U/rat), but not vehicle, LRGILS-NH2 (control peptide), boiled trypsin, or SLIGRL-NH2 injected IP, significantly increased (P < 0.05) abdominal contractions for high volumes of distention, 10- and 24-hour postinfusion. SLIGRL-NH2-induced hyperalgesia was inhibited by a NK1 receptor antagonist (SR 140333) but not by indomethacin. Intracolonic injection of SLIGRL-NH2 elevated spinal Fos expression and caused increased intestinal permeability but did not cause detectable inflammation.


CONCLUSIONS
Intracolonic infusion of subinflammatory doses of PAR-2 agonists activated spinal afferent neurons and produced a delayed rectal hyperalgesia that involves changes in intestinal permeability and the activation of NK1 receptors. These results identify a possible role for proteinases and PAR-2 in the genesis of visceral hyperalgesia.
Coelho
Anne-Marie
AM
Neuro-Gastroenterology and Nutrition Unit, INRA, Toulouse Cedex, France.
Vergnolle
Nathalie
N
Guiard
Bruno
B
Fioramonti
Jean
J
Bueno
Lionel
L
D000818:Animals; D002404:Catheterization; D002614:Chelating Agents / Q000493:pharmacokinetics; D002860:Chromium Radioisotopes; D003092:Colitis / Q000473:pathology; D003106:Colon / Q000294:innervation; D003187:Compliance / Q000187:drug effects; D004492:Edetic Acid / Q000493:pharmacokinetics; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D009475:Neurons, Afferent / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D011453:Prostaglandins / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018179:Receptors, Thrombin / Q000819:agonists / Q000378:metabolism*; D012007:Rectum / Q000294:innervation; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000502:physiology; D013373:Substance P / Q000502:physiology; D014357:Trypsin / Q000494:pharmacology*; D015854:Up-Regulation / Q000502:physiology
D002614:Chelating Agents; D002860:Chromium Radioisotopes; D009842:Oligopeptides; D011453:Prostaglandins; D016760:Proto-Oncogene Proteins c-fos; D044464:Receptor, PAR-2; D018040:Receptors, Neurokinin-1; D018179:Receptors, Thrombin; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; D013373:Substance P; D004492:Edetic Acid; D014357:Trypsin