Impaired defense mechanism against inflammation, hyperalgesia, and airway hyperreactivity in somatostatin 4 receptor gene-deleted mice.
We have shown that somatostatin released from activated capsaicin-sensitive nociceptive nerve endings during inflammatory processes elicits systemic anti-inflammatory and analgesic effects. With the help of somatostatin receptor subtype 4 gene-deleted mice (sst(4)(-/-)), we provide here several lines of evidence that this receptor has a protective role in a variety of inflammatory disease models; several symptoms are more severe in the sst(4) knockout animals than in their wild-type counterparts. Acute carrageenan-induced paw edema and mechanical hyperalgesia, inflammatory pain in the early phase of adjuvant-evoked chronic arthritis, and oxazolone-induced delayed-type hypersensitivity reaction in the skin are much greater in mice lacking the sst(4) receptor. Airway inflammation and consequent bronchial hyperreactivity elicited by intranasal lipopolysaccharide administration are also markedly enhanced in sst(4) knockouts, including increased perivascular/peribronchial edema, neutrophil/macrophage infiltration, mucus-producing goblet cell hyperplasia, myeloperoxidase activity, and IL-1beta, TNF-alpha, and IFN-gamma expression in the inflamed lung. It is concluded that during these inflammatory conditions the released somatostatin has pronounced counterregulatory effects through sst(4) receptor activation. Thus, this receptor is a promising novel target for developing anti-inflammatory, analgesic, and anti-asthmatic drugs.
Helyes
Zsuzsanna
Z
Department of Pharmacology and Pharmacotherapy, Institute of Pharmacognosy, Analgesic Research Laboratory of Gedon Richter Plc., University of Pécs, H-7624 Pécs, Hungary.
Pintér
Erika
E
Sándor
Katalin
K
Elekes
Krisztián
K
Bánvölgyi
Agnes
A
Keszthelyi
Dániel
D
Szoke
Eva
E
Tóth
Dániel M
DM
Sándor
Zoltán
Z
Kereskai
László
L
Pozsgai
Gábor
G
Allen
Jeremy P
JP
Emson
Piers C
PC
Markovics
Adrienn
A
Szolcsányi
János
J
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000209:etiology* / Q000517:prevention & control; D017449:Dermatitis, Allergic Contact / Q000209:etiology; D005260:Female; D006930:Hyperalgesia / Q000209:etiology* / Q000517:prevention & control; D007249:Inflammation / Q000209:etiology* / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010081:Oxazolone / Q000633:toxicity; D017481:Receptors, Somatostatin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D008070:Lipopolysaccharides; D017481:Receptors, Somatostatin; C098681:somatostatin receptor subtype-4; D010081:Oxazolone