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

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 c ancer 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.

Dacarbazine alone or associated with melanoma‐bearing cancer pain model induces painful hypersensitivity by TRPA1 activation in mice

“…TRP channels have been the subject of intense investigation, mainly due to their prevalent localization in a subset of nociceptive sensory neurons . Among them, TRPA1 channel is an essential pain transducer of noxious stimulus (mechanical or thermal), playing a critical role in the perception and transmission of acute and persistent pain conditions, such as inflammation, cancer and neuropathies . Many studies reported TRPA1 involvement in chemotherapy‐induced pain syndrome, including the chemotherapeutic agents, oxaliplatin and cisplatin, bortezomib and paclitaxel …”

“…The antisense oligonucleotide for the TRPA1 receptor to evaluate the involvement of this receptor in dacarbazine‐induced nociception was also used. The animals were treated intrathecally (5 μl/site) with antisense oligonucleotide for TRPA1 (AS TRPA1 ODN, 30 μg) or with mismatch oligonucleotide (MM TRPA1 ODN; 30 μg) three times a day for three consecutive days (Days 11, 12 and 13) after the first dacarbazine administration . Then, mechanical and cold allodynia were evaluated on the 14th day after the first dacarbazine (1 mg/kg/4 days, i.p.)…”

“…or dacarbazine (1 mg/kg/4 days, i.p.) administration . Detailed information are described in the Supporting Information.…”

“…We also evaluated the effect of TRPA1 receptor antagonists on the dacarbazine‐induced hypersensitivity in animals with melanoma. For tumor inoculation, 20 μl of B16‐F10 melanoma cells (2 x 10 5 cells suspended in PBS) were injected subcutaneously into the plantar region of the right hind paw . On the fifth day after tumor inoculation, the animals received vehicle (10 ml/kg, i.p.…”

“…TRPA1 is activated by natural pungent products (e.g., allyl isothiocyanate, allicin and cinnamaldehyde), pollutants (e.g., acrolein and formalin) and endogenous activators (e.g., 4‐hydroxynonenal and hydrogen peroxide), leading to acute pain. TRPA1 mediates mechanical and cold allodynia after inflammatory conditions, cancer or nerve injury, contributing to the development of pathological pain . Furthermore, oxidative factors also contribute to the pain syndrome evoked by chemotherapeutic agents, which may occur by oxidative stress–dependent TRPA1 activation …”