Modulation of capsaicin-evoked visceral pain and referred hyperalgesia by protease-activated receptors 1 and 2.
Protease-activated receptors (PARs) 1 and 2 are expressed in capsaicin-sensitive sensory neurons, being anti- and pro-nociceptive, respectively. Given the possible cross talk between PAR-2 and capsaicin receptors, we investigated if PAR-2 activation could facilitate capsaicin-evoked visceral pain and referred hyperalgesia in the mouse and also examined the effect of PAR-1 activation in this model. Intracolonic (i.col.) administration of capsaicin triggered visceral pain-related nociceptive behavior, followed by referred hyperalgesia. The capsaicin-evoked visceral nociception was suppressed by intraperitoneal (i.p.) TFLLR-NH2, a PAR-1-activating peptide, but not FTLLR-NH2, a control peptide, and unaffected by i.col. TFLLR-NH2. SLIGRL-NH2, a PAR-2-activating peptide, but not LRGILS-NH2, a control peptide, administered i.col., facilitated the capsaicin-evoked visceral nociception 6-18 h after administration, while i.p. SLIGRL-NH2 had no effect. The capsaicin-evoked referred hyperalgesia was augmented by i.col. SLIGRL-NH2, but not LRGILS-NH2, 6-18 h after administration, and unaffected by i.p. SLIGRL-NH2, and i.p. or i.col. TFLLR-NH2. Our data suggest that PAR-1 is antinociceptive in processing of visceral pain, whereas PAR-2 expressed in the colonic luminal surface, upon activation, produces delayed sensitization of capsaicin receptors, resulting in facilitation of visceral pain and referred hyperalgesia.
Kawao
Naoyuki
N
Division of Physiology and Pathophysiology, School of Pharmaceutical Sciences, Kinki University, Osaka, Japan.
Ikeda
Hisao
H
Kitano
Tomoko
T
Kuroda
Ryotaro
R
Sekiguchi
Fumiko
F
Kataoka
Kazuo
K
Kamanaka
Yoshihisa
Y
Kawabata
Atsufumi
A
D000285:Administration, Rectal; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002211:Capsaicin / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D003106:Colon / Q000187:drug effects / Q000294:innervation; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006930:Hyperalgesia / Q000139:chemically induced* / Q000150:complications / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D010146:Pain / Q000139:chemically induced* / Q000150:complications / Q000503:physiopathology; D010147:Pain Measurement / Q000379:methods; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics; D044463:Receptor, PAR-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D044464:Receptor, PAR-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D014781:Viscera / Q000187:drug effects* / Q000294:innervation / Q000503:physiopathology
D009842:Oligopeptides; C462999:PAR-1-activating peptide; D010455:Peptides; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; C497499:leucyl-arginyl-glycyl-isoleucyl-leucyl-serinamide; C497503:phenylalanyl-threonyl-leucyl-leucyl-argininamide; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; C016977:amastatin; D002211:Capsaicin