Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L-menthol and trans-cinnamaldehyde in healthy volunteers.

BACKGROUND: Activation of TRPM8 and TRPA1 receptors generates cold and cold pain sensations, respectively, and is presumably important in clinical pain manifestations, such as cold hyperalgesia. This study investigated the interaction between TRPM8 and TRPA1 receptors through stimulation of glabrous human skin (volar forearm) by topical administration of 40% L-menthol and 10% trans-cinnamaldehyde (CA), individually and in combination. METHODS: Sensory manifestations were assessed in 10 healthy volunteers via a platform of 11 quantitative sensory (thermal and mechanical stimuli) and vasomotor tests (skin temperature, perfusion and axon-reflex-flare) in a double-blinded randomized crossover design. RESULTS: Cold pain threshold was increased (p < 0.01, cold allodynia) by L-menthol alone and L-menthol + CA in combination but unaffected by CA. Mechanical pain threshold was significantly decreased (mechanical hyperalgesia) by all three substances (p < 0.01), with a significant intergroup difference found between CA alone and the less decreased L-menthol + CA (p < 0.05). Application of CA alone and L-menthol + CA in combination showed an increase in skin temperature and perfusion significantly larger than that induced by L-menthol alone (p < 0.05). An axon-reflex-flare was present after CA administration, but was significantly reduced upon addition of L-menthol (p < 0.01). CONCLUSION: This study elucidates the potential of L-menthol as a counter-irritant to secondary neurogenic inflammation and provides evidence of an intricate interplay between cold receptors TRPA1 and TRPM8, warranting further investigation of the neural coding of cold pain perception.

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

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.

Metal artifact reduction sequence: early clinical applications.

Artifact arising from metal hardware remains a significant problem in orthopedic magnetic resonance imaging. The metal artifact reduction sequence (MARS) reduces the size and intensity of susceptibility artifacts from magnetic field distortion. The sequence, which is based on view angle tilting in combination with increased gradient strength, can be conveniently used in conjunction with any spin-echo sequence and requires no additional imaging time. In patients with persistent pain after femoral neck fracture, the MARS technique allows visualization of marrow adjacent to hip screws, thus enabling diagnosis or exclusion of avascular necrosis. Other applications in the hip include assessment of periprosthetic soft tissues after hip joint replacement surgery, postoperative assessment after resection of bone tumors and reconstruction, and localization of unopacified methyl methacrylate cement prior to hip arthroplasty revision surgery. In the knee, the MARS technique allows visualization of structures adjacent to implanted metal staples, pins, or screws. The technique can significantly improve visualization of periprosthetic bone and soft-tissue structures even in patients who have undergone total knee arthroplasty. In patients with spinal fixation hardware, the MARS technique frequently allows visualization of the vertebral bodies and spinal canal contents. The technique can be helpful after wrist fusion or screw fixation of scaphoid fractures.