Transient receptor potential vanilloid 1 mediates hyperalgesia and is up-regulated in rats with chronic pancreatitis.
OBJECTIVE
The neurobiologic basis of pancreatic hyperalgesia in chronic pancreatitis (CP) is understood poorly and there is a need to identify novel therapeutic targets. Our aim was to study the role of the transient receptor potential vanilloid 1 (TRPV1), a key integrator of noxious stimuli, in the pathogenesis of pancreatic pain in a rat model of CP.


METHODS
CP was induced in rats by intraductal injection of trinitrobenzene sulfonic acid. TRPV1 currents in pancreas-specific DRG neurons were measured using perforated patch-clamp techniques. Reverse-transcription polymerase chain reaction was used to measure mRNA expression of TRPV1 in these neurons after laser capture microdissection. Immunofluorescence and Western blot analysis, using TRPV1-specific antibodies, also were performed. Pancreatic hyperalgesia was assessed by rat's nocifensive behavior to electrical stimulation of the pancreas.


RESULTS
CP was associated with a 4-fold increase in capsaicin-induced current density (P < .02), along with an increase in the proportion of pancreas-specific DRG neurons that responded to capsaicin (52.9% in controls vs 79.0% in CP; P < .05). CP also was associated with a significant increase in TRPV1 expression both at the messenger RNA and protein level in whole thoracic DRGs and pancreas-specific sensory neurons. Systemic administration of the TRPV1 antagonist SB-366791 markedly reduced both visceral pain behavior and referred somatic hyperalgesia in rats with CP, but not in control animals.


CONCLUSIONS
TRPV1 up-regulation and sensitization is a specific molecular mechanism contributing to hyperalgesia in CP and represents a useful target for treating pancreatic hyperalgesia caused by inflammation.
Xu
Guang-Yin
GY
Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Winston
John H
JH
Shenoy
Mohan
M
Yin
Huaizhi
H
Pendyala
Swaroop
S
Pasricha
Pankaj Jay
PJ
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010179:Pancreas / Q000294:innervation*; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid; D015854:Up-Regulation
D000813:Anilides; D002934:Cinnamates; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D012333:RNA, Messenger; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014302:Trinitrobenzenesulfonic Acid; D002211:Capsaicin