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Int J Cancer. 2019 Jan 15;144(2):355-365. doi: 10.1002/ijc.31911. Epub 2018 Oct 30.

Transient receptor potential ankyrin 1 (TRPA1) plays a critical role in a mouse model of cancer pain.

Author information

1
Graduate Program in Pharmacology, Federal University of Santa Maria (UFSM), Santa Maria, Rio Grande do Sul, Brazil.
2
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
3
Graduate Program in Health Science, University of the Extreme South of Santa Catarina, Unesc, Criciúma, Santa Catarina, Brazil.
4
Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria (UFSM), Santa Maria, Rio Grande do Sul, Brazil.
5
Biochemistry and genetics Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.
6
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
7
Graduate Program in Pharmacology, Federal University of Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil.

Abstract

There is a major, unmet need for the treatment of cancer pain, and new targets and medicines are required. The transient receptor potential ankyrin 1 (TRPA1), a cation channel expressed by nociceptors, is activated by oxidizing substances to mediate pain-like responses in models of inflammatory and neuropathic pain. As cancer is known to increase oxidative stress, the role of TRPA1 was evaluated in a mouse model of cancer pain. Fourteen days after injection of B16-F10 murine melanoma cells into the plantar region of the right hind paw, C57BL/6 mice exhibited mechanical and thermal allodynia and thigmotaxis behavior. While heat allodynia was partially reduced in TRP vanilloid 1 (TRPV1)-deficient mice, thigmotaxis behavior and mechanical and cold allodynia were absent in TRPA1-deficient mice. Deletion of TRPA1 or TRPV1 did not affect cancer growth. Intrathecal TRPA1 antisense oligonucleotides and two different TRPA1 antagonists (HC-030031 or A967079) transiently attenuated thigmotaxis behavior and mechanical and cold allodynia. A TRPV1 antagonist (capsazepine) attenuated solely heat allodynia. NADPH oxidase activity and hydrogen peroxide levels were increased in hind paw skin 14 days after cancer cell inoculation. The antioxidant, α-lipoic acid, attenuated mechanical and cold allodynia and thigmotaxis behavior, but not heat allodynia. Whereas TRPV1, via an oxidative stress-independent pathway, contributes partially to heat hypersensitivity, oxidative stress-dependent activation of TRPA1 plays a key role in mediating thigmotaxis behavior and mechanical and cold allodynia in a cancer pain model. TRPA1 antagonists might be beneficial in the treatment of cancer pain.

KEYWORDS:

HC-030031; NADPH oxidase; allodynia; chemotherapeutic drugs; hydrogen peroxide

PMID:
30289972
DOI:
10.1002/ijc.31911
[Indexed for MEDLINE]

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