Peripheral and spinal TRPA1 channels contribute to formalin-induced long-lasting mechanical hypersensitivity

Abstract

Vladimir A Martínez-Rojas,1 Guadalupe García,1 Roxana Noriega-Navarro,1 Crystell G Guzmán-Priego,2 Jorge E Torres-López,2,3 Vinicio Granados-Soto,4 Janet Murbartián1 1Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Unidad Coapa, Ciudad de México, 2Laboratorio Mecanismos del Dolor, Centro de Investigación, División Académica de Ciencias de la Salud, Universidad Juárez Autónoma de Tabasco, 3Hospital Regional de Alta Especialidad “Dr. Juan Graham Casasús”, Villahermosa, Tabasco, 4Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, Unidad Coapa, Ciudad de México, México Background: Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel expressed by a subset of nociceptive neurons that acts as a multimodal receptor. Its activity contributes to modulate nociceptive transmission in acute inflammatory pain. However, the role of this channel in chronic pain has been less studied. The purpose of this study was to investigate the local peripheral and spinal participation of TRPA1 channels in formalin-induced long-lasting hypersensitivity.Materials and methods: Formalin (1%)-induced chronic hypersensitivity was determined by the application of von Frey filaments to ipsilateral and contralateral paws and through pharmacological testing using a selective TRPA1 blocker (A-967079). TRPA1 expression in the dorsal root ganglion (DRG) and spinal cord was analyzed by Western blotting.Results: Formalin (1%) injection produced acute flinching behavior (1 h) as well as secondary allodynia and hyperalgesia (12 days). Local peripheral pretreatment (10 min before) or posttreatment (6 days later) with A-967079 (1–100 µM) partially prevented and reversed, respectively, in a dose-dependent manner, long-lasting secondary mechanical allodynia and hyperalgesia evoked by 1% formalin. Likewise, intrathecal pretreatment or posttreatment with A-967079 partially prevented and reversed, respectively, formalin-induced long-lasting hypersensitivity. A-967079 (100 µM) completely abolished the pro-nociceptive effect of formalin (adjusted to pH 7.4). Finally, formalin injection increased TRPA1 protein expression in the DRG and spinal cord.Conclusion: Results indicate that TRPA1 expressed in the DRG and spinal cord plays a relevant role in formalin-induced long-lasting secondary nociceptive hypersensitivity. Keywords: allodynia, chronic pain, formalin, hyperalgesia, TRPA1

Keywords

• Allodynia
• Chronic pain
• Formalin
• Hyperalgesia
• TRPA1.