Transient receptor potential vanilloid (TRPV-1) promotes neurogenic inflammation in the pancreas via activation of the neurokinin-1 receptor (NK-1R).
OBJECTIVE
The transient receptor potential vanilloid 1 (TRPV-1) is an ion channel found on primary sensory afferent neurons. Activation of TRPV-1 leads to the release of the proinflammatory neuropeptide substance P (SP). SP then binds to the neurokinin-1 receptor (NK1-R) on endothelial cells and promotes extravasation of plasma and proteins into the interstitial tissue and neutrophil infiltration, a process called neurogenic inflammation. We tested 2 hypotheses: (1) activation of TRPV-1 in the pancreas leads to interstitial edema and neutrophil infiltration and (2) TRPV-1-induced plasma extravasation is mediated by the release of SP and activation of the NK1-R in the rat.


METHODS
We measured extravasation of the intravascular tracer Evans blue as an index of plasma extravasation and quantified pancreas tissue myeloperoxidase activity (MPO) as a marker of neutrophil infiltration. The severity of inflammation following intravenous infusion of the secretagogue cerulein (10 microg/kg/h x 4 hours) was assessed using a histologic scoring system.


RESULTS
Intravenous injection of the TRPV-1 agonist capsaicin induced a dose-dependent increase in Evans blue accumulation in the rat pancreas (P < 0.05 vs. vehicle control). This effect was blocked by pretreatment with the TRPV-1 antagonist capsazepine (1.8 mg/kg), or the NK1-R antagonist CP 96,345 (1 mg/kg). Capsazepine also reduced cerulein-induced Evans blue, MPO, and histologic severity of inflammation in the pancreas but had no effect on serum amylase.


CONCLUSIONS
Activation of TRPV-1 induces SP-mediated plasma extravasation in the rat pancreas via activation of the NK1-R. TRPV-1 mediates neurogenic inflammation in cerulein-induced pancreatitis in the rat.
Hutter
Matthew M
MM
Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
Wick
Elizabeth C
EC
Day
Amy Lightner
AL
Maa
John
J
Zerega
Elena C
EC
Richmond
Alec C
AC
Jordan
Thomas H
TH
Grady
Eileen F
EF
Mulvihill
Sean J
SJ
Bunnett
Nigel W
NW
Kirkwood
Kimberly S
KS
D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002108:Ceruletide; D004396:Coloring Agents / Q000493:pharmacokinetics; D005070:Evans Blue / Q000493:pharmacokinetics; D008297:Male; D009443:Neuritis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D010179:Pancreas / Q000276:immunology / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*
D004396:Coloring Agents; D018040:Receptors, Neurokinin-1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D005070:Evans Blue; D002108:Ceruletide; C071423:capsazepine; D002211:Capsaicin