The somatostatin receptor 4 agonist J-2156 reduces mechanosensitivity of peripheral nerve afferents and spinal neurons in an inflammatory pain model

• Published in: European journal of pharmacology 2015-01, Vol.746, p.274-281
• Main Authors: Schuelert, Niklas, Just, Stefan, Kuelzer, Raimund, Corradini, Laura, Gorham, Louise C.J., Doods, Henri
• Format: Article
• Language: English
• Subjects: Administration, Cutaneous; Analgesics, Non-Narcotic - administration & dosage; Analgesics, Non-Narcotic - blood; Analgesics, Non-Narcotic - pharmacokinetics; Analgesics, Non-Narcotic - therapeutic use; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - blood; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Behavior, Animal - drug effects; Butanes - administration & dosage; Butanes - blood; Butanes - pharmacokinetics; Butanes - therapeutic use; Disease Models, Animal; Dose-Response Relationship, Drug; Electrophysiological Phenomena - drug effects; Hyperalgesia - blood; Hyperalgesia - drug therapy; Hyperalgesia - immunology; Hyperalgesia - metabolism; In vivo electrophysiology; Inflammatory pain; Injections, Intraperitoneal; Injections, Intravenous; Male; Mechanoreceptors - drug effects; Mechanoreceptors - immunology; Mechanoreceptors - metabolism; Naphthalenes - administration & dosage; Naphthalenes - blood; Naphthalenes - pharmacokinetics; Naphthalenes - therapeutic use; Neuritis - blood; Neuritis - drug therapy; Neuritis - immunology; Neuritis - metabolism; Neurons, Afferent - drug effects; Neurons, Afferent - immunology; Neurons, Afferent - metabolism; Nociceptors - drug effects; Nociceptors - immunology; Nociceptors - metabolism; Peripheral Nerves - drug effects; Peripheral Nerves - immunology; Peripheral Nerves - metabolism; Primary afferent; Rat; Rats, Wistar; Receptors, Somatostatin - agonists; Receptors, Somatostatin - metabolism; Somatostatin receptor 4; Spinal cord; Spinal Nerves - drug effects; Spinal Nerves - immunology; Spinal Nerves - metabolism; Sulfones - administration & dosage; Sulfones - blood; Sulfones - pharmacokinetics; Sulfones - therapeutic use
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2014.11.003

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 24h 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 0.1mg/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 100µM 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.