Abnormal cold-evoked pain is a characteristic symptom [11] in some patients with neuropathic pain. In some pathologies, like for example oxaliplatin-induced neuropathy, hypersensitivity (allodynia) to normally innocuous cold stimuli is a very frequent complaint [1]. The structural and functional mechanisms underlying cold-evoked pain are currently unclear. Some authors hypothesize a peripheral origin (ie, alteration in nociceptor function) while others suggest that alterations in the central processing of cold afferent signals are critical. Obviously, the two mechanisms are not mutually exclusive. Clarifying this issue is not only important for proper management of this disabling symptom but also remains a current therapeutic challenge for clinicians. In part, the uncertainties clouding our understanding of cold-evoked pain are due to the lack of detailed clinical reports, including microneurographic recordings. When studying cold-evoked responses, this powerful technique, which explores directly the activity of peripheral somatosensory afferents [4], has been used mainly in experimental subjects.

The study by Serra and colleagues, published in this issue of Pain [12], albeit limited to just one young female patient complaining of intense cold-evoked burning pain, describes some intriguing pathophysiological findings and microneurographic characterization of sensory fibers. The report represents a significant step forward in our understanding of cold allodynia in humans. In contrast with the lack of spontaneous activity characteristic of healthy individuals, in this patient, many C-type nociceptors fired spontaneously. This finding may explain the spontaneous burning pain, also documented in other neuropathic conditions. Furthermore, some units with a microneurographic signature of nociceptors, also responded to innocuous cold and menthol. Responses to mild cold temperatures and menthol are generally associated with activation of specific cold thermoreceptors [10]. In these sensory receptors, activation of TRPM8 ion channels plays a critical role as these are key molecular transducers of cold temperature [7, 9]. Responses to menthol in identified nociceptors raises the question whether TRPM8 channels do not merely signal innocuous cooling sensations, but are also involved in signalling cold pain. Evidence for the possible involvement of TRPM8 channels in noxious cold sensations is slowly trickling into the neuroscience literature (reviewed by [2]). Thus, mice lacking TRPM8 show reduced responses in nerve injury induced models of cold-allodynia. In these mice, sensory fibers with high threshold cold-evoked responses are difficult to record from electrophysiologically. Moreover, TRPM8-positive fibers are prominent in peripheral territories with marked noxious responses to cold. Many neurons responding to TRPM8 agonists are also activated by capsaicin, a marker of nociceptors. Finally, application of menthol to the skin or mucosae can be described as irritating or painful rather than