Investigation of the analgesic effects of new non-antibiotic tetracycline derivatives on mechanical allodynia and thermal hyperalgesia in a preclinical model of trigeminal neuralgia

• Grant number: 23/14005-6
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2025
• End date: March 31, 2027
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Glauce Crivelaro Do Nascimento
• Grantee: Glauce Crivelaro Do Nascimento
• Host Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Bruna Balbino de Paula ; Daniela Escobar ; Elaine Aparecida Del Bel Belluz Guimarães ; Luiz Guilherme de Siqueira Branco ; Patrick Pierre Michel ; Rita Raisman-Vozari

Abstract

The injury of the trigeminal nerve reflects the most debilitating form of facial neuralgia. In trigeminal neuralgia, the painful condition sets in and disappears suddenly, reappearing at different intervals triggered by harmless stimuli across the trigeminal nerve's sensory area. The pathophysiology of this condition involves structural and functional changes at both central and peripheral levels, and often the symptoms are resistant to treatment. Previous studies suggest that tetracyclines (TCs) possess interesting analgesic properties. We will test here whether such properties could be found in newly synthesized TCs without antibiotic activity in a trigeminal neuralgia model (in vivo) and in trigeminal ganglion cells challenged by an inflammatory environment (in vitro).Using the infraorbital branch constriction model in rats (Wistar - 250g), we will test the effects of DDMC (5, 10, 20mg/kg, s.c.) and DDOX (10, 20, 40mg/kg, s.c.), two compounds which are non-antibiotic derivatives of demeclocycline and doxycycline, respectively. Abundant literature suggests that neuroinflammation plays a crucial role in the induction and maintenance of chronic pain. Increasing evidence also indicates that pro-inflammatory cytokines and chemokines produced by astrocytes and microglia control the release of astrocytic glutamate and might specifically contribute to the loss of glutamate transporters' (GluTs) function, thereby facilitating central sensitization during neuropathic pain development and maintenance. Molecular modulation of GluTs could thus become a prospective therapeutic approach for managing pain in trigeminal neuralgia. Therefore, this study aims to analyze in vivo the effects of DDMC and DDOX on (i) orofacial mechanical allodynia and thermal hyperalgesia responses; (ii) neuroinflammatory changes in the trigeminal ganglion (GT) and spinal trigeminal nucleus (Sp5): glial cell activation, PGE2, TNF-±, IL-1², IL-6, BDNF, CGRP, Substance P; (iii) alterations in glutamatergic signaling caused by inflammatory factors produced in GT and Sp5. Additionally, the effects of DDMC and DDOX will be investigated on (iv) the glutamatergic signaling of GT cells in culture challenged with inflammatory agents. The findings of this study will advance the understanding of the anti-nociceptive effects of tetracyclines unrelated to their antibiotic activity and the comprehension of trigeminal neurophysiology, which collectively will aid in the search for new therapeutic targets for treating trigeminal nerve neuralgia. (AU)