Dose–response study of topical allyl isothiocyanate (mustard oil) as a human surrogate model of pain, hyperalgesia, and neurogenic inflammation

Abstract

Despite being a ubiquitous animal pain model, the natural TRPA1-agonist allyl isothiocyanate (AITC, also known as "mustard oil") has only been sparsely investigated as a potential human surrogate model of pain, sensitization, and neurogenic inflammation. Its dose-response as an algogenic, sensitizing irritant remains to be elucidated in human skin. Three concentrations of AITC (10%, 50%, and 90%) and vehicle (paraffin) were applied for 5 minutes to 3 × 3 cm areas on the volar forearms in 14 healthy volunteers, and evoked pain intensity (visual analog scale 0-100 mm) and pain quality were assessed. In addition, a comprehensive battery of quantitative sensory tests was conducted, including assessment of mechanical and thermal sensitivity. Neurogenic inflammation was quantified using full-field laser perfusion imaging. Erythema and hyperpigmentation were assessed before, immediately after, and ≈64 hours after AITC exposure. AITC induced significant dose-dependent, moderate-to-severe spontaneous burning pain, mechanical and heat hyperalgesia, and dynamic mechanical allodynia (P < 0.05). No significant differences in induced pain hypersensitivity were observed between the 50% and 90% AITC concentrations. Acute and prolonged inflammation was evoked by all concentrations, and assessments by full-field laser perfusion imaging demonstrated a significant dose-dependent increase with a ceiling effect from 50% to 90%. Topical AITC application produces pain and somatosensory sensitization in a dose-dependent manner with optimal concentrations recommended to be >10% and ≤50%. The model is translatable to humans and could be useful in pharmacological proof-of-concept studies of TRPA1-antagonists, analgesics, and anti-inflammatory compounds or for exploratory clinical purposes, eg, loss- or gain-of-function in peripheral neuropathies.

Psychophysical and vasomotor evidence for interdependency of TRPA1 and TRPV1-evoked nociceptive responses in human skin: an experimental study

“…The AITC (Sigma Aldrich, Brøndby, Denmark) was dissolved in 99% pharmaceutical grade paraffin (Løve Apoteket, Aalborg, Denmark) at a concentration of 10% AITC (vol/vol). This concentration was determined from previous studies 49,77 , including a recently published dose-response study 10 . Capsaicin was dissolved in a solution of 30% deionized water and 70% ethanol at a concentration of 1% (10mg/mL; Skanderborg Apotek, Denmark).…”

“…While capsaicin activates TRPV1, allyl isothiocyanate (AITC), also known as mustard oil (MO) activates TRPA1 10 . TRPV1 is evidently more densely expressed in rodent dorsal root ganglion (DRG) nociceptors than TRPA1 but the two receptors do exhibit substantial co-expression.…”

Effects of allyl isothiocyanate on insulin resistance, oxidative stress status, and transcription factors in high‐fat diet/streptozotocin‐induced type 2 diabetes mellitus in rats

“…Medical plants and their bioactive components are widely used worldwide for the management of DM and complications due to their nontoxic nature, obtainability, and affordability. One of them, Allyl isothiocyanate (AITC), a natural compound found in many vegetables, has been reported to possess antiobesity, antimicrobial, anticancer and analgesic and anti‐inflammatory properties. AITC inhibits hepatic gluconeogenesis and ameliorates insulin resistance .…”

A Human TRPA1-Specific Pain Model

“…Previous studies of TRPA1-related human pain models investigated at best TRPA1 among other targets, mainly due to the lack of a selective agonist, where specificity can hardly be claimed. AITC, for instance, was injected in 1-9 M (10 -90%) concentration in psychophysical experiments (Andersen et al, 2017). Concentrations Ͼ100 M, however, were found to activate TRPV1 as well, and at higher concentrations in the millimolar range the activation of TRPV1 exceeds TRPA1 by many times, as the latter can even be inhibited again (Everaerts et al, 2011;Gees et al, 2013;Meseguer et al, 2014).…”

“…Previously described chemical stimulation of TRPA1 in human subjects has used substances which are known to coactivate other targets. For example, allyl isothiocyanate (AITC) was recently used for a TRPA1-dependent pain model (Andersen et al, 2017); however, AITC can also activate TRPV1 (Gees et al, 2013). According to the reported EC 50 of 0.65 nM, 2-chloro-N-(4-(4methoxyphenyl)thiazol-2-yl)-N-(3-methoxypropyl)-acetamide (JT010) was the most potent commercially available agonist (Takaya et al, 2015).…”