Attenuation of persistent experimental pancreatitis pain by a bradykinin b2 receptor antagonist.
OBJECTIVE
The role of bradykinin (BK) receptors in activating and sensitizing peripheral nociceptors is well known. Recently, we showed that spinal dynorphin was pronociceptive through direct or indirect BK receptor activation. Here, we explored the potential role of BK receptors in pain associated with persistent pancreatitis in rats.


METHODS
Experimental pancreatitis and abdominal hypersensitivity were induced by intravenous administrations of dibutyltin dichloride (DBTC). [des-Arg-Leu]BK (B1 antagonist) and HOE 140 (B2 antagonist) were given by intraperitoneal or intrathecal injection. Dynorphin antiserum was given intrathecally. Reverse transcription-polymerase chain reaction was used to detect spinal mRNA for BK receptors.


RESULTS
Dibutyltin dichloride-induced pancreatitis upregulated B1 and B2 mRNA in the thoracic dorsal root ganglion and B2, but not B1, in the pancreas. No changes in spinal B1 or B2 mRNA were observed. Intraperitoneal or intrathecal administration of HOE 140 dose dependently abolished DBTC-induced abdominal hypersensitivity, whereas [des-Arg-Leu]BK was without effect by either route of administration. Antiserum to dynorphin (intrathecal) abolished DBTC-induced hypersensitivity.


CONCLUSIONS
These results suggest that blockade of peripheral or spinal BK B2 receptors may be an effective approach for diminishing pain associated with pancreatitis. Moreover, it is suggested that spinal dynorphin may maintain pancreatitis pain through direct or indirect activation of BK B2 receptors in the spinal cord.
Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ 85724, USA.
Qingmin
Q
Chen
Louis P
LP
Vera-Portocarrero
Michael H
MH
Ossipov
Marina
M
Vardanyan
Josephine
J
Lai
Frank
F
Porreca
D015746:Abdominal Pain / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D004399:Dynorphins / Q000276:immunology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007106:Immune Sera / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007278:Injections, Spinal; D008297:Male; D009947:Organotin Compounds / Q000008:administration & dosage / Q000633:toxicity; D010146:Pain / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D007106:Immune Sera; D009947:Organotin Compounds; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; C051090:bradykinin, Leu(8)-des-Arg(9)-; D004399:Dynorphins; C065679:icatibant; C020735:dibutyldichlorotin; D001920:Bradykinin