Antipruritic Effect of Cold-induced and Transient Receptor Potential-agonist-induced Counter-irritation on Histaminergic Itch in Humans

Abstract

A frequent empirical observation is that cold-induced counter-irritation may attenuate itch. The aim of this randomized, single-blinded, exploratory study was to evaluate the counter-irritation effects of cold-stimulation and topical application of transient receptor potential TRPA1/M8-agonists (trans-cinnamaldehyde/L-menthol, respectively), on histamine-induced itch, wheals and neurogenic inflammation in 13 healthy volunteers. Histamine 1% was applied to the volar forearms using skin prick-test lancets. Recorded outcome-parameters were itch intensity, wheal reactions, and neurogenic inflammation (measured by laser-speckle perfusion-imaging). Homotopic thermal counter-irritation was performed with 6 temperatures, ranging from 4°C to 37°C, using a 3 × 3-cm thermal stimulator. Chemical "cold-like" counter-irritation was conducted with 40% L-menthol and 10% trans-cinnamaldehyde, while 5% doxepin was used as a positive antipruritic control/comparator. Cold counter-irritation stimuli from 4°C to 22°C inhibited itch in a stimulus-intensity-dependent manner (p < 0.05) and, to a lesser extent, also wheal reactions and neurogenic inflammation. Chemical "cold-like" counter-irritation with both L-menthol and trans-cinnamaldehyde had antipruritic efficacy similar to doxepin (p < 0.05). Cold-induced counter-irritation had an inhibitory effect on histaminergic itch, suggesting that agonists of cold transduction receptors could be of potential antipruritic value.

Histaminergic and non‐histaminergic elicited itch is attenuated in capsaicin‐evoked areas of allodynia and hyperalgesia: A healthy volunteer study

“…As a result, the study was not directed towards quantifying the histaminergic itch, that is, both histamine-induced itch provocations were performed and assessed simultaneously, histamine were delivered close to the capsaicin injection by i.d. Given that even mild homotopic painful stimuli are capable of greatly reducing itch (Graham et al, 1951;Yosipovitch et al, 2005Yosipovitch et al, , 2007Kosteletzky et al, 2009;Andersen et al, 2017a), it is hard to evaluate whether the observed itch reduction was related to capsaicin-induced secondary sensitization or simply ongoing counter-stimulation. Applying this methodology, the study reported that only 2/8 tested subjects reported itch when histamine injections were given in allodynic skin as opposed to normal skin, which is in some accordance with the reduction in itch sensation observed in the present experiment.…”

“…The pronounced and well-documented inhibition of itch by homotopic pain can be readily elicited, for example, by scratching or by applying noxious heat stimuli in an area with ongoing itch (Graham et al, 1951;Yosipovitch et al, 2005Yosipovitch et al, , 2007Kosteletzky et al, 2009;Andersen et al, 2017a). This inhibitory mechanism is suggested to rely on spinal basic-helixloop-helix B5-interneurons and a population of vesicular glutamate transporter type 2-expressing neurons activated by nociceptive stimuli and inhibiting spinal transmission of pruriceptive signaling (Lagerstr€ om et al, 2010;Liu et al, 2010;Ross et al, 2010;Ross, 2011).…”

Antipruritic effects of transient heat stimulation on histaminergic and nonhistaminergic itch

“…However, numerous studies suggest that homotopic innocuous and noxious cooling, or cooling compounds are capable of suppressing itch, and patients with chronic itch frequently report that cooling relieves their itch. 21,50,68,69 This warrants further investigation. In experiment 2, itch intensity without any counterstimuli was not assessed.…”

“…Moreover, the effect of transient cold stimuli was not investigated in this study due to technical limitations. However, numerous studies suggest that homotopic innocuous and noxious cooling, or cooling compounds are capable of suppressing itch, and patients with chronic itch frequently report that cooling relieves their itch . This warrants further investigation.…”

Extraoral Taste Receptor Discovery: New Light on Ayurvedic Pharmacology

“…TRPA1, TRPV4, and TRPV3 expressions were increased in burn scars with postburn pruritus [101]. Although, in terms of pharmacological activity, science differentiates between cooling and heating pungent compounds: cooling pungent compounds (TRPM8 agonists, e.g., menthol) ameliorate pruritus [322], while heating pungent compounds (TRPV1 agonists, capsaicin) aggravates it [323]. Scientists had recently suggested that agonists of cold transduction receptors might have antipruritic potential [322].…”