Effects of the somatostatin receptor subtype 4 selective agonist J-2156 on sensory neuropeptide release and inflammatory reactions in rodents.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY 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 AND IMPLICATIONS:

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.

• Authors: Z Helyes, E Pintér, J Németh, K Sándor, K Elekes, A Szabó, G Pozsgai, D Keszthelyi, L Kereskai, M Engström, S Wurster, J Szolcsányi
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 149 Issue 4 Pg. 405-15 (Oct 2006) ISSN: 0007-1188 [Print] England
• PMID: 16953190 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Butanes
• Lipopolysaccharides
• Membrane Proteins
• Naphthalenes
• Neuropeptides
• Plant Oils
• Receptors, Somatostatin
• Sulfones
• somatostatin receptor subtype-4
• Carrageenan
• (1'S, 2S)-4-amino-N-(1'-carbamoyl-2'-phenylethyl)-2-(4''-methyl-1''-naphthalenesulfonylamino)butanamide
• mustard oil

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Arthritis, Experimental (prevention & control)
• Butanes (pharmacology, therapeutic use)
• Carrageenan
• Dose-Response Relationship, Drug
• Edema (chemically induced, prevention & control)
• Electric Stimulation
• Inflammation (chemically induced, metabolism, prevention & control)
• Lipopolysaccharides
• Male
• Membrane Proteins (agonists, metabolism)
• Mice
• Mice, Inbred BALB C
• Mustard Plant
• Naphthalenes (pharmacology, therapeutic use)
• Neurogenic Inflammation (prevention & control)
• Neuropeptides (metabolism)
• Plant Oils
• Pulmonary Eosinophilia (chemically induced, prevention & control)
• Rats
• Rats, Inbred Lew
• Rats, Wistar
• Receptors, Somatostatin (agonists, metabolism)
• Sulfones (pharmacology, therapeutic use)
• Trachea (drug effects, metabolism)