RESUMO
Neuropathic pain is a chronic pain characterized by injury to the central or peripheral nervous system and that most often causes disability in individuals. Among the mechanisms involved in central sensitization during neuropathic pain are cytokines and chemokines released by spinal glial cells; however, these mechanisms are not well elucidated. Thus, the present study aimed to investigate the involvement of Chemokine (C-X-C motif) ligand 1 (CXCL1) and glial cells in this process. Male Wistar rats weighing 220-240 g were used and underwent a neuropathic pain model induced by chronic constriction injury (CCI). To investigate the involvement of CXCL1, chemokine receptor type 2 (CXCR2), mitogen-activated protein kinases (MAPK) p38, and microglia and astrocytes, the following drugs were used: SB225002, an CXCR2 antagonist; SML0543, a MAPK p38 inhibitor; minocycline, a microglia inhibitor; fluorocitrate, an astrocytes inhibitor; and recombinant CXCL1. The microglia, astrocytes, CXCL1, and MAPK p38 protein levels was evaluated by a Western blot assay. Furthermore, an immunofluorescence assay was performed to localize microglia and astrocytes immunoreactivity in the spinal cord. The results demonstrated that both CCI and CXCL1 induced nociception, and this effect was reversed by SB225002. In addition, minocycline, fluorocitrate, and SML0543 reversed the mechanical allodynia induced by CCI. Furthermore, there was an increase of spinal CXCL1 and microglial marker Iba1 protein levels , which was reversed by SB225002. This antagonist also reduced the Iba1 immunoreactivity in spinal cord. Thus, the present study suggests that the CXCL1 chemokine participates in neuropathic pain through CXCR2 activation in spinal microglia.
Assuntos
Quimiocina CXCL1/metabolismo , Microglia/metabolismo , Neuralgia/patologia , Nociceptividade/fisiologia , Medula Espinal/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Quimiocina CXCL1/administração & dosagem , Citratos/administração & dosagem , Modelos Animais de Doenças , Humanos , Injeções Espinhais , Masculino , Microglia/efeitos dos fármacos , Minociclina/administração & dosagem , Neuralgia/induzido quimicamente , Nociceptividade/efeitos dos fármacos , Compostos de Fenilureia/administração & dosagem , Ratos , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/metabolismo , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Transcutaneous electrical nerve stimulation (TENS) promotes antinociception by activating the descending pain modulation pathway and consequently releasing endogenous analgesic substances. In addition, recent studies have shown that the endocannabinoid system controls pain. Thus, the present study investigated the involvement of the endocannabinoid system in TENS-induced antinociception of cancer pain using a cancer pain model induced by intraplantar (i.pl.) injections of Ehrlich tumor cells in male Swiss mice. Low- and high-frequency TENS was applied for 20 minutes to the mice's paws, and to investigate the involvement of the endocannabinoid system were used the N-(peperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pitazole-3-carboixamide (AM251), a cannabinoid CB1 receptor antagonist and (5Z,8Z,11Z,14Z)-5,8,11,14-eicosatetraenyl-methylester phosphonofluoridic acid (MAFP), an inhibitor of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase, injected by via i.pl., intrathecal (i.t.), and intradorsolateral periaqueductal gray matter (i.dl.PAG). Furthermore, liquid chromatography-tandem mass spectrometry, western blot, and immunofluorescence assays were used to evaluate the endocannabinoid anandamide levels, cannabinoid CB1 receptor protein levels, and cannabinoid CB1 receptor immunoreactivity, respectively. Low- and high-frequency TENS reduced the mechanical allodynia induced by Ehrlich tumor cells and this effect was reversed by AM251 and potentiated by MAFP at the peripheral and central levels. In addition, TENS increased the endocannabinoid anandamide levels and the cannabinoid CB1 receptor protein levels and immunoreactivity in the paw, spinal cord, and dorsolateral periaqueductal gray matter. These results suggest that low- and high-frequency TENS is effective in controlling cancer pain, and the endocannabinoid system is involved in this effect at both the peripheral and central levels. PERSPECTIVE: TENS is a nonpharmacological strategy that may be used to control cancer pain. Identification of a new mechanism involved in its analgesic effect could lead to the development of clinical studies as well as an increase in its application, lessening the need for pharmacological treatments.
Assuntos
Dor do Câncer/terapia , Antagonistas de Receptores de Canabinoides/farmacologia , Endocanabinoides/metabolismo , Inibidores Enzimáticos/farmacologia , Hiperalgesia/terapia , Estimulação Elétrica Nervosa Transcutânea , Animais , Ácidos Araquidônicos/farmacologia , Dor do Câncer/metabolismo , Antagonistas de Receptores de Canabinoides/administração & dosagem , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Hiperalgesia/metabolismo , Masculino , Camundongos , Organofosfonatos/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidoresRESUMO
Introdução: O câncer tem sido um crescente problema de saúde pública no Brasil. Comumente, a pessoa com câncer pode apresentar diversas alterações posturais, como a rotação da pelve, ocasionadas pela doença e por efeitos adversos secundários às formas de tratamento. Objetivo: Analisar a influência do posicionamento rotacional da pelve de pessoas com câncer por meio da baropodometria. Métodos: Foram incluídos 45 indivíduos, divididos em: Grupo Quimioterapia e/ou Radioterapia (GQR), Grupo Câncer em Acompanhamento (GCA) e Grupo Controle sem Câncer (GCS). Todos os voluntários foram avaliados quanto ao posicionamento da pelve por meio da baropodometria. Resultados: Não foram encontradas alterações significativas no posicionamento rotacional da pelve nas comparações entre os grupos com câncer e grupo controle (p: 0,112; Poder: 0,838; f2: 1,121). Conclusão: Os resultados sugerem que o câncer e suas formas de tratamento não exerceram influência sobre a postura rotacional da pelve. (AU)
Introduction: Cancer has been a growing public health problem in Brazil. Patients with cancer may commonly present a number postural changes such as the pelvis rotation due to the disease itself and also to secondary adverse effects produced by its forms of treatment. Objective: To assess the rotational positioning of the pelvis in cancer patients using computerized baropodometry. Methods: A total of 45 volunteers were divided into: Chemotherapy combined with radiotherapy Group (QRG), Follow up Cancer Group (CAG) and Control Group without Cancer (CG). All subjects were assessed for the positioning of the pelvis using baropodometry Results: No significant changes were found in the rotational positioning of the pelvis in the comparison between the cancer groups and the control group (p: 0,112; Power: 0,838; Effect: 1,121). Conclusion: The results suggest that the cancer and its forms of treatment have no influence on the rotational posture of the pelvis. (AU)