FRI0011 5-ht2b receptor antagonists reduce inflammation and pain

Abstract

Background Serotonin (5-HT) is well known as a central neurotransmitter, but has important functions also in the periphery, e.g. as a regulator of vascular tone, platelet aggregation and cytokine expression. Objectives The aim of this study was to investigate the potential influence of selective 5-HT2B receptor antagonists on inflammation and inflammatory pain. For this purpose, AnaMar´s proprietary compounds were studied in vitro and in vivo. Methods In vitro, IL-6 production: Primary synoviocytes were isolated from pannus tissue obtained from female, Dark Agouti rats with antigen-induced arthritis and used for experiments after seven days in culture. The cells were stimulated with 5-HT and LPS, in the presence of the 5-HT2B receptor antagonists (0.1-10 µM). After three days incubation, supernatants were collected and the IL-6 content measured with ELISA. In vivo, systemic inflammation: Female BALB/c mice were pre-treated perorally with the 5-HT2B receptor antagonists (3-30 mg/kg). Thirty minutes later, LPS was administered systemically by intra-peritoneal injection. After 90 minutes, blood was collected and cytokines measured in plasma with ELISA. In vivo, inflammatory pain: Male Sprague-Dawley rats were pre-treated perorally with the 5-HT2B receptor antagonists (3-30 mg/kg). Sixty minutes later, formalin was injected subcutaneously into the dorsum of the right hind paw to induce pain. Pain responses were recorded by measuring the cumulative time of nociceptive behaviour per unit of time. Results AnaMar´s 5-HT2B receptor antagonists dose-dependently decreased the production of IL-6 from primary rat synoviocytes. Further, the compounds potently decreased the production of TNF-α triggered by systemic LPS injection in mice. In the inflammatory pain model, the compounds significantly reduced the pain response. Conclusions The 5-HT2B receptor antagonists reduced inflammatory cytokine production and pain responses. The results strongly support that approaches targeting 5-HT2B receptor signaling could have therapeutic potential in conditions associated with inflammation and inflammatory pain. It remains to be investigated whether the effect on inflammatory pain is mediated through a suppressed production of inflammatory cytokines, a direct effect on peripheral neurons, or a combination of these. References Mössner R, Lesch KP: Role of serotonin in the immune system and in neuroimmune interactions, Brain Behav Immun 1998, 12 (4): 249-271. Disclosure of Interest N. Palmqvist Employee of: AnaMar AB, C. Wenglén Employee of: AnaMar AB, A. Sjödin Employee of: AnaMar AB, A.-C. Ryde Employee of: AnaMar AB, M. Siller Employee of: AnaMar AB, H. Arozenius Employee of: AnaMar AB, A. Mathisson Employee of: AnaMar AB, C. Klint Employee of: AnaMar AB, A. Pramhed Employee of: AnaMar AB, L. Pettersson Employee of: AnaMar AB, G. Ekström Employee of: AnaMar AB