Cold and L-menthol-induced sensitization in healthy volunteers—a cold hypersensitivity analogue to the heat/capsaicin model

Abstract

Topical high-concentration L-menthol is the only established human experimental pain model to study mechanisms underlying cold hyperalgesia. We aimed at investigating the combinatorial effect of cold stimuli and topical L-menthol on cold pain and secondary mechanical hyperalgesia. Analogue to the heat-capsaicin model on skin sensitization, we proposed that cold/menthol enhances or prolong L-menthol-evoked sensitization. Topical 40% L-menthol or vehicle was applied (20 minutes) on the volar forearms of 20 healthy females and males (age, 28.7 ± 0.6 years). Cold stimulation of 5°C for 5 minutes was then applied to the treated area 3 times with 40-minute intervals. Cold detection threshold and pain, mechanical hyperalgesia (pinprick), static and dynamic mechanical allodynia (von Frey and brush), skin blood flow (laser speckle), and temperature (thermocamera) were assessed. Cold detection threshold and cold pain threshold (CPT) increased after L-menthol and remained high after the cold rekindling cycles (P < 0.001). L-menthol evoked secondary hyperalgesia to pinprick (P < 0.001) particularly in females (P < 0.05) and also induced secondary allodynia to von Frey and brush (P < 0.001). Application of cold stimuli kept these areas enlarged with a higher response in females to brush after the third cold cycle (P < 0.05). Skin blood flow increased after L-menthol (P < 0.001) and stayed stable after cold cycles. Repeated application of cold on skin treated by L-menthol facilitated and prolonged L-menthol-induced cold pain and hyperalgesia. This model may prove beneficial for testing analgesic compounds when a sufficient duration of time is needed to see drug effects on CPT or mechanical hypersensitivity.

Cutaneous TRPM8-expressing sensory afferents are a small population of neurons with unique firing properties

“…; Andersen et al. ). The location of the area of skin treated with Menthol was recorded on a photograph of the skin and any subsequent cells with receptive fields overlapping one of these areas were not included in this study.…”

High-Concentration L-Menthol Exhibits Counter-Irritancy to Neurogenic Inflammation, Thermal and Mechanical Hyperalgesia Caused by Trans-cinnamaldehyde

“…21,33,45,63 Not previously shown, co-administration of Lmenthol decreased the SH established by CA. Since SH is generally recognized to be a centrally mediated mechanism 2,30,48 , this is likely a consequence of an overall diminished nociceptive drive, i.e. through decreased spontaneous pain and neurogenic inflammation.…”

Impact of suggestion on the human experimental model of cold hyperalgesia after topical application of high‐concentration menthol [40%]

“…The human‐evoked pain models used for this study induce symptoms and signs that are neuropathic‐like (Klein et al., ; Andersen et al., ). However recently, it was clearly shown that only a limited subset of pain models predicts efficacy of analgesics in a clinical situation (Lotsch et al., ).…”

“…The topical application of menthol has been characterized and evaluated thoroughly as a human experimental model of pain and hyperalgesia (Klein et al., ; Mahn et al., ; Andersen et al., , ). Menthol induces cold and mechanical hyperalgesia (Klein et al., ) and activates the transient receptor potential (TRP) melastin 8 (TRPM8; de la Torre‐Martinez et al., ) channel leading to activation and sensitization of afferent nociceptive neurons (Klein et al., ).…”

“…Previous trials in healthy human subjects demonstrated that the topical application of menthol at a high concentration [40%] is suitable as an experimental model of cold and mechanical (pinprick) hyperalgesia (Wasner et al., ; Binder et al., ; Roberts et al., ; Andersen et al., , ; Mahn et al., ; Forster et al., ). Pharmacological intervention with ibuprofen, tramadol and pregabalin showed significantly reduced cold hyperalgesia only for tramadol in this model (Altis et al., ).…”