title: The somatostatin receptor 4 agonist J-2156 reduces mechanosensitivity of peripheral nerve afferents and spinal neurons in an inflammatory pain model.
abstract: Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotransmission via interaction with G protein-coupled SST receptors and inhibition of the release of different hormones. The aim of this study was to investigate whether the analgesic properties of the selective SSTR4 agonist J-2156 are mediated via peripheral and/or spinal receptors. Effect on mechanical hyperalgesia in the Complete Freund׳s Adjuvant (CFA) model was measured after intraperitoneal application of J-2156. Electrophysiological neuronal recordings were conducted 24 h after injection of CFA or vehicle into the paw of Wistar rats. Mechanosensitivity of peripheral afferents of the saphenous nerve as well as of spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were measured after systemic or spinal application of J-2156. In CFA animals J-2156 dose dependently reduced hyperalgesia in behavioral studies. The minimal effective dose was 0.1 mg/kg. Mechanosensitivity of peripheral afferents and spinal neurons was significantly reduced by J-2156. NS neurons were dose dependently inhibited by J-2156 while in WDR neurons only the highest concentration of 100 µM had an effect. In sham controls, J-2156 had no effect on neuronal activity. We demonstrated that J-2156 dose-dependently reduces peripheral and spinal neuronal excitability in the CFA rat model without affecting physiological pain transmission. Given the high concentration of the compound required to inhibit spinal neurons, it is unlikely that the behavioral effect seen in CFA model is mediated centrally. Overall these data demonstrated that the analgesic effect of J-2156 is mediated mainly via peripheral SST4 receptors.
authors.affiliation: Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany. Electronic address: niklas.schuelert@boehringer-ingelheim.com.
authors.forename: Niklas
authors.initials: N
authors.lastname: Schuelert
authors.affiliation: Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Just
authors.affiliation: Department of Drug Discovery and Support, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany.
authors.forename: Raimund
authors.initials: R
authors.lastname: Kuelzer
authors.affiliation: Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Corradini
authors.affiliation: Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany.
authors.forename: Louise C J
authors.initials: LC
authors.lastname: Gorham
authors.affiliation: Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany.
authors.forename: Henri
authors.initials: H
authors.lastname: Doods
mesh_terms: D000279:Administration, Cutaneous; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002073:Butanes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006930:Hyperalgesia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009281:Naphthalenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009443:Neuritis / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010525:Peripheral Nerves / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000378:metabolism; D013127:Spinal Nerves / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002073:Butanes; D009281:Naphthalenes; D017481:Receptors, Somatostatin; D013450:Sulfones; C098681:somatostatin receptor subtype-4; C499293:(1'S, 2S)-4-amino-N-(1'-carbamoyl-2'-phenylethyl)-2-(4''-methyl-1''-naphthalenesulfonylamino)butanamide
keywords: In vivo electrophysiology; Inflammatory pain; Primary afferent; Rat; Somatostatin receptor 4; Spinal cord