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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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

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Neuropeptides
Rodentia
Interleukin-1
Calcitonin Gene-Related Peptide
Substance P
Somatostatin
Neurogenic Inflammation
Evans Blue
Granulocytes
Endotoxins
Peroxidase
Arthritis
Anti-Inflammatory Agents
Lung
Skin
Zymosan
Experimental Arthritis
Carrageenan
Capsaicin
Bradykinin

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{38d5098ee3664f93a3df9cacf0d21a7d,
title = "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 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.",
keywords = "Adjuvant-induced arthritis, Capsaicin-sensitive sensory nerves, Endotoxininduced airway inflammation, Neurogenic inflammation, Oedema, Somatostatin sst receptors",
author = "Z. Helyes and E. Pint{\'e}r and J. N{\'e}meth and K. S{\'a}ndor and K. Elekes and {\'A} Szab{\'o} and G. Pozsgai and D. Keszthelyi and L. Kereskai and M. Engstr{\"o}m and S. Wurster and J. Szolcs{\'a}nyi",
year = "2006",
month = "10",
day = "11",
doi = "10.1038/sj.bjp.0706876",
language = "English",
volume = "149",
pages = "405--415",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Effects of the somatostatin receptor subtype 4 selective agonist J-2156 on sensory neuropeptide release and inflammatory reactions in rodents

AU - Helyes, Z.

AU - Pintér, E.

AU - Németh, J.

AU - Sándor, K.

AU - Elekes, K.

AU - Szabó, Á

AU - Pozsgai, G.

AU - Keszthelyi, D.

AU - Kereskai, L.

AU - Engström, M.

AU - Wurster, S.

AU - Szolcsányi, J.

PY - 2006/10/11

Y1 - 2006/10/11

N2 - 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.

AB - 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.

KW - Adjuvant-induced arthritis

KW - Capsaicin-sensitive sensory nerves

KW - Endotoxininduced airway inflammation

KW - Neurogenic inflammation

KW - Oedema

KW - Somatostatin sst receptors

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