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J Pain. 2019 Nov 27. pii: S1526-5900(19)30868-5. doi: 10.1016/j.jpain.2019.11.009. [Epub ahead of print]

Investigation of the Involvement of the Endocannabinoid System in TENS-induced Antinociception.

Author information

1
Sciences of Motricity Institute, Federal University of Alfenas, Jovino Fernandes Sales Ave, 2600, 37130-000, Alfenas, Brazil.
2
Department of Physiology, Federal University of Minas Gerais, Antônio Carlos Ave., 6627, 31270-901, Belo Horizonte, Brazil.
3
Faculty of Pharmaceutical Sciences of Ribeirão Preto, Universidade de São Paulo, Café Ave., room 93, Brazil.
4
Department of Pathology, Federal University of Minas Gerais, Antônio Carlos Ave., 6627, 31270-901, Belo Horizonte, Brazil.
5
Sciences of Motricity Institute, Federal University of Alfenas, Jovino Fernandes Sales Ave, 2600, 37130-000, Alfenas, Brazil. Electronic address: galdinoggs@zipmail.com.br.

Abstract

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 min 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 intra-dorsolateral periaqueductal gray matter (i.dl.PAG). Furthermore, liquid chromatography-tandem mass spectrometry, western blot, and immunofluorescence assays were used to evaluate the endocannabinoid anandamide (AEA) 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 AEA levels and the cannabinoid CB1 receptor protein levels and immunoreactivity in the paw, spinal cord, and dorsolateral PAG. 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 non-pharmacological 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.

KEYWORDS:

Endocannabinoids; TENS; antinociception; cancer pain; mechanical allodynia

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