Maresin-2 inhibits inflammatory and neuropathic trigeminal pain and reduces neuronal activation in the trigeminal ganglion

Raphael Vieira Lopes; Darciane Favero Baggio; Camila Rodrigues Ferraz; Mariana Marques Bertozzi; Telma Saraiva-Santos; Waldiceu Aparecido Verri Junior; Juliana Geremias Chichorro

doi:10.1016/j.crneur.2023.100093

Maresin-2 inhibits inflammatory and neuropathic trigeminal pain and reduces neuronal activation in the trigeminal ganglion

Curr Res Neurobiol. 2023 Jun 8:4:100093. doi: 10.1016/j.crneur.2023.100093. eCollection 2023.

Authors

Raphael Vieira Lopes¹, Darciane Favero Baggio¹, Camila Rodrigues Ferraz², Mariana Marques Bertozzi², Telma Saraiva-Santos², Waldiceu Aparecido Verri Junior², Juliana Geremias Chichorro¹

Affiliations

¹ Department of Pharmacology, Biological Sciences Sector, Federal University of Parana, Curitiba, Parana, Brazil.
² Laboratory of Pain, Inflammation, Neuropathy and Cancer, Department of Pathology, State University of Londrina, Londrina, PR, Brazil.

Abstract

Pain is a common symptom associated with disorders involving the orofacial structures. Most acute orofacial painful conditions are easily recognized, but the pharmacological treatment may be limited by the adverse events of current available drugs and/or patients' characteristics. In addition, chronic orofacial pain conditions represent clinical challenges both, in terms of diagnostic and treatment. There is growing evidence that specialized pro-resolution lipid mediators (SPMs) present potent analgesic effects, in addition to their well characterized role in the resolution of inflammation. Maresins (MaR-1 and MaR-2) were the last described members of this family, and MaR-2 analgesic action has not yet been reported. Herein the effect of MaR-2 in different orofacial pain models was investigated. MaR-2 (1 or 10 ng) was always delivered via medullary subarachnoid injection, which corresponds to the intrathecal treatment. A single injection of MaR-2 caused a significant reduction of phases I and II of the orofacial formalin test in rats. Repeated injections of MaR-2 prevented the development of facial heat and mechanical hyperalgesia in a model of post-operative pain in rats. In a model of trigeminal neuropathic pain (CCI-ION), repeated MaR-2 injections reversed facial heat and mechanical hyperalgesia in rats and mice. CCI-ION increased c-Fos positive neurons and CGRP⁺ activated (nuclear pNFkB) neurons in the trigeminal ganglion (TG), which were restored to sham levels by MaR-2 repeated treatment. In conclusion, MaR-2 showed potent and long-lasting analgesic effects in inflammatory and neuropathic pain of orofacial origin and the inhibition of CGRP-positive neurons in the TG may account for MaR-2 action.

Keywords: CGRP; Chronic constriction injury of the infraorbital nerve; Formalin test; Hyperalgesia; Intraoral incision; Mice; Rats; Specialized pro-resolution lipids; c-Fos.