A review of topical high‐concentration L‐menthol as a translational model of cold allodynia and hyperalgesia

Abstract

Background: Cold allodynia and cold hyperalgesia are both elusive features of neuropathic pain, particularly in patients with various polyneuropathies. Numerous studies have suggested that topical application of L-menthol causes temporary cold hypersensitivity and thus acts as a proxy for associated symptoms. This review summarizes studies on L-menthol-induced nociception, cold allodynia and cold hyperalgesia in vitro, in animals and in humans. Methods: A comprehensive literature search was performed using the PubMed and Google Scholar databases until February 2013. Obtained manuscripts were reviewed for relevancy and reference lists of the retrieved articles were cross-checked for additional important studies. Solely the literature regarding topical application of L-menthol in humans was attained systematically. Of the total identified studies (96), 10 met the inclusion criteria being controlled studies applying L-menthol at a concentration of ≥30%. Results: The extracted data are meticulously compared and presented with emphasis on clarity and transparency. In seven animal studies, cold allodynia or hyperalgesia was successfully established utilizing various methods. Eight studies in healthy volunteers unanimously reported a significant increase in cold pain threshold, representing cold allodynia and increased supra-threshold cold pain sensitivity, thus demonstrating cold hyperalgesia. Conclusions: Topical high-concentration L-menthol consistently induces cold hypersensitivity in animals and humans, thus constituting a predictable surrogate model of cold allodynia and hyperalgesia. Understanding translational features of this model and its underlying mechanisms could be valuable in preclinical and human phases of drug development and in improving current treatment of patients with polyneuropathy.

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

“…In the present study we sought to evaluate the analgesic, anti-hyperalgesic and antiinflammatory effect of L-menthol to CA-induced sensory and vasomotor symptomatology, and as such did not include a condition with L-menthol alone, which is well known to induce prolonged cold hyperalgesia, spontaneous pain and primary and secondary hyperalgesia. 3,8,34,43,50,62,63 Topical application of 10% CA provoked mild pain, primary and secondary mechanical hyperalgesia, heat and cold hyperalgesia and substantial primary and secondary neurogenic inflammation. Notably, 3 subjects were considerably below the averagely reported pain peak values and scored ≤ 1 (0.80 ± 0.05) on the VAS versus 3.87 ± 0.46, for the remaining 11 subjects.…”

“…Ethanol was chosen as a vehicle because of 1) its ability to dissolve a high concentration of L-menthol, 2) its low toxicity for an organic solvent, 3) its marginal somatosensory sensory effects and 4) the precedence of using it in literature. 3,4,39,40,43 …”

“…Paradoxically, numerous recent studies (reviewed in 3 ) describing the somatosensory alterations induced by high concentrations of topical L-menthol have found that the substance is capable of inducing prolonged cold hyperalgesia, spontaneous pain and primary and secondary hyperalgesia. As such, labeling L-menthol as a counter-irritant is seemingly more accurate than labeling it as a local anesthetic.…”

Low-level laser therapy alleviates mechanical and cold allodynia induced by oxaliplatin administration in rats

“…Each animal received a total of four injections with either oxaliplatin or vehicle, administered at 3-day intervals (days 1, 4, 7, and 10). Laser or sham irradiation was started 4 h after the first oxaliplatin/vehicle administration and continued for 12 consecutive days (one session per day, days [1][2][3][4][5][6][7][8][9][10][11][12]. Sensory behavior and general toxicity were assessed on the days before each administration of oxaliplatin/vehicle (days 0, 3, 6, and 9), and after all laser irradiation treatments were completed (day 12).…”

“…Transient receptor potential cation channel subfamily M member 8 (TRPM8) protein, also known as the cold and menthol receptor 1, is expressed in sensory neurons of DRG and activated by cold temperatures and cooling agents such as menthol and icilin [7,8]. Recently, accumulating evidence indicates that the TRPM8 protein is involved in acute oxaliplatin-induced neuropathy [9,10].…”