Transient receptor potential vanilloid 1, calcitonin gene-related peptide, and substance P mediate nociception in acute pancreatitis.
The mechanism of pancreatitis-induced pain is unknown. In other tissues, inflammation activates transient receptor potential vanilloid 1 (TRPV1) on sensory nerves to liberate CGRP and substance P (SP) in peripheral tissues and the dorsal horn to cause neurogenic inflammation and pain, respectively. We evaluated the contribution of TRPV1, CGRP, and SP to pancreatic pain in rats. TRPV1, CGRP, and SP were coexpressed in nerve fibers of the pancreas. Injection of the TRPV1 agonist capsaicin into the pancreatic duct induced endocytosis of the neurokinin 1 receptor in spinal neurons in the dorsal horn (T10), indicative of SP release upon stimulation of pancreatic sensory nerves. Induction of necrotizing pancreatitis by treatment with L-arginine caused a 12-fold increase in the number of spinal neurons expressing the proto-oncogene c-fos in laminae I and II of L1, suggesting activation of nociceptive pathways. L-arginine also caused a threefold increase in spontaneous abdominal contractions detected by electromyography, suggestive of referred pain. Systemic administration of the TRPV1 antagonist capsazepine inhibited c-fos expression by 2.5-fold and abdominal contractions by 4-fold. Intrathecal, but not systemic, administration of antagonists of CGRP (CGRP(8-37)) and SP (SR140333) receptors attenuated c-fos expression in spinal neurons by twofold. Thus necrotizing pancreatitis activates TRPV1 on pancreatic sensory nerves to release SP and CGRP in the dorsal horn, resulting in nociception. Antagonism of TRPV1, SP, and CGRP receptors may suppress pancreatitis pain.
Wick
Elizabeth C
EC
Departments of Surgery and Physiology, Univ. of California-San Francisco, 521 Parnassus Avenue, Rm C341, San Francisco, CA 94143-0790, USA.
Hoge
Steven G
SG
Grahn
Sarah W
SW
Kim
Edward
E
Divino
Lorna A
LA
Grady
Eileen F
EF
Bunnett
Nigel W
NW
Kirkwood
Kimberly S
KS
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology; D008297:Male; D009475:Neurons, Afferent / Q000378:metabolism; D010146:Pain / Q000209:etiology*; D010147:Pain Measurement / Q000379:methods; D010179:Pancreas / Q000294:innervation*; D010195:Pancreatitis / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism; D013127:Spinal Nerves / Q000378:metabolism; D013373:Substance P / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018015:Receptors, Calcitonin Gene-Related Peptide; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D013373:Substance P; D001120:Arginine; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin