de Oliveira Herick Ulisses, Dos Santos Rafaela Silva, Malta Iago Henrique Silva, Pinho José Phellipe, Almeida Ana Flávia Santos, Sorgi Carlos Arterio, Peti Ana Paula Ferranti, Xavier Gabriela Santos, Reis Luciana Maria Dos, Faccioli Lúcia Helena, Cruz Jader Dos Santos, Ferreira Enio, Galdino Giovane
Sciences of Motricity Institute, Federal University of Alfenas, Alfenas, Brazil.
Department of Physiology, Federal University of Minas Gerais, Belo Horizonte, Brazil.
J Pain. 2020 Jul-Aug;21(7-8):820-835. doi: 10.1016/j.jpain.2019.11.009. Epub 2019 Nov 27.
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 CB 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 CB receptor protein levels, and cannabinoid CB 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 CB 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.
经皮电刺激神经疗法（TENS）通过激活下行性疼痛调制通路并因此释放内源性镇痛物质来促进抗伤害感受。此外，最近的研究表明，内源性大麻素系统可控制疼痛。因此，本研究使用雄性瑞士小鼠足底注射艾氏腹水癌细胞诱导的癌痛模型，研究内源性大麻素系统在TENS诱导的癌痛抗伤害感受中的作用。将低频和高频TENS施加于小鼠爪部20分钟，为研究内源性大麻素系统的作用，使用了N-（哌啶-1-基）-5-（4-碘苯基）-1-（2,4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺（AM251），一种大麻素CB受体拮抗剂，以及（5Z,8Z,11Z,14Z）-5,8,11,14-二十碳四烯基-甲基酯膦酰氟（MAFP），一种内源性大麻素代谢酶脂肪酸酰胺水解酶的抑制剂，并通过足底、鞘内和导水管周围灰质背外侧注射。此外，分别使用液相色谱-串联质谱法、蛋白质印迹法和免疫荧光测定法来评估内源性大麻素花生四烯乙醇胺水平、大麻素CB受体蛋白水平和大麻素CB受体免疫反应性。低频和高频TENS减轻了艾氏腹水癌细胞诱导的机械性异常性疼痛，并且在周围和中枢水平上，AM251可逆转这种作用，而MAFP可增强这种作用。此外，TENS增加了爪部、脊髓和导水管周围灰质背外侧的内源性大麻素花生四烯乙醇胺水平、大麻素CB受体蛋白水平和免疫反应性。这些结果表明，低频和高频TENS在控制癌痛方面有效，并且内源性大麻素系统在周围和中枢水平均参与了这种作用。观点：TENS是一种可用于控制癌痛的非药物策略。确定其镇痛作用中涉及的新机制可能会促使开展临床研究，并增加其应用，从而减少药物治疗的需求。
