SHORT COMMUNICATION Pro-inflammatory cytokines involvement in the hesperidin antihyperalgesic effects at peripheral and central levels in a neuropathic pain model A. I. Carballo-Villalobos 1,2,4 • M. E. Gonza ´lez-Trujano 2,4 • N. Alvarado-Va ´zquez 3 • F. J. Lo ´pez-Mun ˜oz 1 Received: 12 October 2016 / Accepted: 11 February 2017 Ó Springer International Publishing 2017 Abstract Emerging evidence proposes a link between immune changes and pain, which is consistent with the inflammation theory and the increased incidence of neu- rodegenerative diseases. Flavonoids have long been used because of their anti-inflammatory potential activity and they are considered a promising alternative to alleviate neuropathic pain. The aim of this study was to investigate the antihyperalgesic effect of hesperidin and the presence of pro-inflammatory cytokines evaluated at peripheral and central levels in the chronic constriction injury as model of neuropathic pain in rats. Mechanical and thermal hyperal- gesia were assessed in the aesthesiometer and plantar tests, respectively, as related to the presence of cytokines con- centrations (TNF-a, IL-1b and IL-6) in sciatic nerve and segments of the spinal cord after 15 days chronic con- striction injury model in rats receiving vehicle or hesperidin. Antihyperalgesic response of hesperidin (100 mg/kg) was associated to the presence of cytokines mainly at several sections of the spinal cord suggesting not only peripheral but also its involvement in central sensiti- zation in the experimental neuropathic pain. Keywords Central sensitization Á Cytokines Á Flavonoids Á Hesperidin Á Neuropathic pain Á Peripheral sensitization Introduction Neuroinflammatory response is a pivotal component of the mechanisms underlying pathological peripheral and central neuropathic pain (Scholz and Woolf 2007). The experi- mental studies have provided evidence that the pro- inflammatory cytokines can induce or facilitate this kind of pain (Old et al. 2015). In fact, cytokines are recognized as signaling proteins and intercellular messengers in immune reaction against the nervous system injury playing a crucial role in neuroinflammatory processes (Scholz and Woolf 2007), where tumor necrosis factor (TNF)-a, interleukin (IL)-1b and IL-6 have been strongly involved in the pathogenesis of neuropathy (Kiguchi et al. 2012). Flavonoids have long been used because of their anti- inflammatory potential activity and they are considered a promising alternative to alleviate neuropathic pain (Quin- tans et al. 2014). In the case of hesperidin (hesperetin-7- rhamnoglucoside), it is a citrus flavonoid that has been reported not only to have attenuated hyperglycemia but also reversed pain in rats with diabetic neuropathy by a reduction in the pro-inflammatory cytokines (TNF-a and IL-1b) (Visnagri et al. 2014). In a similar manner, hes- peretin (aglicone of hesperidin) decreased hyperalgesia and allodynia involving modulation of TNF-a, IL-1b and IL-6 in a model of partial sciatic nerve ligation (Aswar et al. & M. E. Gonza ´lez-Trujano evag@imp.edu.mx 1 Laboratorio No.7 ‘‘Dolor y Analgesia’’ del Departamento de Farmacobiologı ´a, Cinvestav-Sede Sur, Calz. de los Tenorios No. 235, Col. Granjas Coapa, CP 14330 Me ´xico, D.F., Mexico 2 Laboratorio de Neurofarmacologı ´a de Productos Naturales de la Direccio ´n de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatrı ´a ‘‘Ramo ´n de la Fuente Mun ˜iz’’, Av. Me ´xico-Xochimilco No. 101, Col. San Lorenzo Huipulco, 14370 Me ´xico, D.F., Mexico 3 Departamento de Bioquı ´mica, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Calzada de Tlalpan 4502, Col. Seccio ´n XVI, CP 14080 Me ´xico, D.F., Mexico 4 Facultad de Quı ´mica, Universidad Nacional Auto ´noma de Me ´xico, Circuito exterior S/N, Ciudad Universitaria, Me ´xico 04510, Mexico Inflammopharmacol DOI 10.1007/s10787-017-0326-3 Inflammopharmacology 123