Topical treatment with a transient receptor potential ankyrin 1 (TRPA1) antagonist reduced nociception and inflammation in a thermal lesion model in rats

Abstract

Thermal injury promotes tissue inflammation and pain, which is difficult to control. Different peripheral mechanisms seem to be involved in burn pain, such as free radical-induced damage, but further study is still needed to understand how oxidant substances induced nociceptor sensitization. The transient receptor potential ankyrin 1 (TRPA1) is an ion channel activated by oxidants substances, and it could be sensitized after tissue inflammation. This study evaluated the TRPA1 involvement in nociception and inflammation produced by a thermal injury model. Male Wistar rats were used. The concentration of the TRPA1 antagonist (HC-030031, 0.05%) on base cream was chosen using allyl isothiocyanate intraplantar test. Then, the base cream containing HC-030031 was tested on the thermal injury model (induced by warm water immersion of hind paw, under anesthesia), and silver sulfadiazine (1%) was used as a positive control. Cream treatments on the hind paw were done daily (200 mg/paw) for 6 days after thermal injury. Also, nociception (static and dynamic mechanical allodynia, heat allodynia, and spontaneous pain) or edema were evaluated. On day 6, inflammatory and oxidative parameters were assessed. The base cream containing HC-030031 produced antinociceptive and anti-inflammatory effects (reduced the edema and inflammatory cells infiltration) and decreased the levels of hydrogen peroxide, or superoxide dismutase and NADPH oxidase activities after thermal injury. Thus, this study showed the involvement of the TRPA1 receptor in the nociception and inflammation caused by thermal injury and suggested that TRPA1 antagonists might be useful as novel treatments for pain and inflammation by topical application.

Advances in TRP channel drug discovery: from target validation to clinical studies

“…Topical administration may help overcome such prob lems. Indeed, a topical HC030031 gel (0.05%) reversed mechanical and cold allodynia in mice after ultraviolet B induced burn injury 90 . This implies a therapeutic value for TRPA1 antagonist creams for patients with sunburn pain or thermal injury.…”

Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease

“…TRPA1 ablation results in reduced inflammation and fibrosis/scarring in the corneal stroma during wound healing (626). At the level of the skin, it was recently shown that HC-030031 has antinociceptive and anti-inflammatory effects after thermal injury (183,287). (457,735,736,823,849), where it is involved in the spontaneous peptide hormone exocytosis (800) and its ablation decreases mature oligodendrocyte apoptosis and thereby demyelination and behavioral alterations and morphological changes induced by cuprizone (115,700).…”

<p>Intrathecal TRPM8 blocking attenuates cold hyperalgesia via PKC and NF-&kappa;B signaling in the dorsal root ganglion of rats with neuropathic pain</p>

“…TRPM8 expression may directly influence the thermal pain threshold given that TRPM8 blocker reduced TRPM8 expression in CCI rats (Figure 2). There may be correlations between TRPM8 and other thermo-sensitive receptors, such as Nav1.7,33 TRPA134 and TRPV1,35 which need further research to detect the expression of these receptors when TRPM8 was blocked.…”