Effects of the somatostatin receptor subtype 4 selective agonist J-2156 on sensory neuropeptide release and inflammatory reactions in rodents.
OBJECTIVE
Substance P (SP) and calcitonin gene-related peptide (CGRP) released from capsaicin-sensitive sensory nerves induce local neurogenic inflammation; somatostatin exerts systemic anti-inflammatory actions presumably via sst4/sst1 receptors. This study investigates the effects of a high affinity, sst4-selective, synthetic agonist, J-2156, on sensory neuropeptide release in vitro and inflammatory processes in vivo.


METHODS
Electrically-induced SP, CGRP and somatostatin release from isolated rat tracheae was measured with radioimmunoassay. Mustard oil-induced neurogenic inflammation in rat hindpaw skin was determined by Evans blue leakage and in the mouse ear with micrometry. Dextran-, carrageenan- or bradykinin-induced non-neurogenic inflammation was examined with plethysmometry or Evans blue, respectively. Adjuvant-induced chronic arthritis was assessed by plethysmometry and histological scoring. Granulocyte accumulation was determined with myeloperoxidase assay and IL-1beta with ELISA.


RESULTS
J-2156 (10-2000 nM) diminished electrically-evoked neuropeptide release in a concentration-dependent manner. EC50 for the inhibition of substance P, CGRP and somatostatin release were 11.6 nM, 14.3 nM and 110.7 nM, respectively. J-2156 (1-100 microg kg(-1) i.p.) significantly, but not dose-dependently, inhibited neurogenic and non-neurogenic acute inflammatory processes and adjuvant-induced chronic oedema and arthritic changes. Endotoxin-evoked myeloperoxidase activity and IL-1beta production in the lung, but not IL-1beta- or zymosan-induced leukocyte accumulation in the skin were significantly diminished by J-2156.


CONCLUSIONS
J-2156 acting on sst4 receptors inhibits neuropeptide release, vascular components of acute inflammatory processes, endotoxin-induced granulocyte accumulation and IL-1beta synthesis in the lung and synovial and inflammatory cells in chronic arthritis. Therefore it might be a promising lead for the development of novel anti-inflammatory drugs.
Helyes
Z
Z
Department of Pharmacology and Pharmacotherapy, University of Pécs, Pécs, Szigeti u. 12, Hungary. zsuzsanna.helyes@aok.pte.hu
Pintér
E
E
Németh
J
J
Sándor
K
K
Elekes
K
K
Szabó
A
A
Pozsgai
G
G
Keszthelyi
D
D
Kereskai
L
L
Engström
M
M
Wurster
S
S
Szolcsányi
J
J
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000517:prevention & control; D002073:Butanes / Q000494:pharmacology* / Q000627:therapeutic use; D002351:Carrageenan; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004558:Electric Stimulation; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008070:Lipopolysaccharides; D008297:Male; D008565:Membrane Proteins / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009149:Mustard Plant; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D020078:Neurogenic Inflammation / Q000517:prevention & control; D009479:Neuropeptides / Q000378:metabolism*; D010938:Plant Oils; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D002073:Butanes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009281:Naphthalenes; D009479:Neuropeptides; D010938:Plant Oils; D017481:Receptors, Somatostatin; D013450:Sulfones; C098681:somatostatin receptor subtype-4; D002351:Carrageenan; C499293:(1'S, 2S)-4-amino-N-(1'-carbamoyl-2'-phenylethyl)-2-(4''-methyl-1''-naphthalenesulfonylamino)butanamide; C027793:mustard oil