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

Z. Helyes, E. Pintér, J. Németh, K. Sándor, K. Elekes, Á Szabó, G. Pozsgai, D. Keszthelyi, L. Kereskai, M. Engström, S. Wurster, J. Szolcsányi

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41 Citations (Scopus)

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 sst 4/sst 1 receptors. This study investigates the effects of a high affinity, sst 4-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-1β with ELISA. Key results: J-2156 (10-2000nM) diminished electrically-evoked neuropeptide release in a concentration-dependent manner. EC 50 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 μg 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-1β production in the lung, but not IL-1β- or zymosan-induced leukocyte accumulation in the skin were significantly diminished by J-2156. Conclusions and implications: J-2156 acting on sst 4 receptors inhibits neuropeptide release, vascular components of acute inflammatory processes, endotoxin-induced granulocyte accumulation and IL-1β 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.

Original languageEnglish
Pages (from-to)405-415
Number of pages11
JournalBritish journal of pharmacology
Volume149
Issue number4
DOIs
Publication statusPublished - Oct 11 2006

Keywords

  • Adjuvant-induced arthritis
  • Capsaicin-sensitive sensory nerves
  • Endotoxininduced airway inflammation
  • Neurogenic inflammation
  • Oedema
  • Somatostatin sst receptors

ASJC Scopus subject areas

  • Pharmacology

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