Phosphorylation of ERK in the spinal dorsal horn following pancreatic pronociceptive stimuli with proteinase-activated receptor-2 agonists and hydrogen sulfide in rats: evidence for involvement of distinct mechanisms.
Noxious stimuli cause prompt phosphorylation of extracellular signal-regulated kinase (ERK) in the spinal dorsal horn that contributes to facilitation of pain sensation and is often used as an immediate marker for excitation of spinal neurons following somatic and colonic nociception. Here we asked whether two distinct pronociceptive stimuli with proteinase-activated receptor-2 (PAR2) agonists and hydrogen sulfide (H(2)S) in the pancreas cause phosphorylation of ERK in the spinal dorsal horn and also examined involvement of their possible downstream signaling molecules, transient receptor potential vanilloid-1 (TRPV1) and T-type Ca(2+) channels, respectively. Capsaicin (a TRPV1 agonist), trypsin (an endogenous PAR2 agonist), SLIGRL-NH(2) (a PAR2-activating peptide), and NaHS (an H(2)S donor) were infused into the pancreatic duct in anesthetized rats, and phosphorylated ERK in the spinal cord was detected by immunohistochemistry. Intraductal administration of capsaicin and trypsin caused prompt phosphorylation of ERK in the superficial layers of T9, but not T5 or T12, spinal dorsal horn. SLIGRL-NH(2) and NaHS, administered in the same manner, also produced ERK phosphorylation in the corresponding spinal regions. Mibefradil, a T-type Ca(2+) channel blocker, abolished the phosphorylation of ERK caused by intraductal NaHS but not SLIGRL-NH(2). In contrast, capsazepine, an inhibitor of TRPV1, suppressed the phosphorylation of ERK caused by intraductal SLIGRL-NH(2) but not NaHS. Our data thus demonstrate that pancreatic pronociceptive stimuli with PAR2 agonists and H(2)S cause ERK phosphorylation in the spinal dorsal horn, through activation of TRPV1 and T-type Ca(2+) channels, respectively, and that those two pronociceptive pathways are independent of each other.
Fukushima
Osamu
O
Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka, Japan.
Nishimura
Sachiyo
S
Matsunami
Maho
M
Aoki
Yuka
Y
Nishikawa
Hiroyuki
H
Ishikura
Hiroyasu
H
Kawabata
Atsufumi
A
D000818:Animals; D002121:Calcium Channel Blockers / Q000633:toxicity; D002211:Capsaicin / Q000031:analogs & derivatives / Q000633:toxicity; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006862:Hydrogen Sulfide / Q000633:toxicity*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009619:Nociceptors / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010148:Intractable Pain / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D010183:Pancreatic Ducts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000819:agonists* / Q000502:physiology*
D002121:Calcium Channel Blockers; D044464:Receptor, PAR-2; D048049:Extracellular Signal-Regulated MAP Kinases; C071423:capsazepine; D002211:Capsaicin; D006862:Hydrogen Sulfide