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Chronic pain associated with injury or disease can result from dysfunction of sensory afferents whereby the threshold for activation of pain-sensing neurons (nociceptors) is lowered. Neurotrophic factors control nociceptor development and survival, but also induce sensitization through activation of their cognate receptors, attributable, in part, to the modulation of ion channel function. Thermal pain is mediated by channels of the transient receptor potential (TRP) family, including the cold and menthol receptor TRPM8. Although it has been shown that TRPM8 is involved in cold hypersensitivity, the molecular mechanisms underlying this pain modality are unknown. Using microarray analyses to identify mouse genes enriched in TRPM8 neurons, we found that the glial cell line-derived neurotrophic factor (GDNF) family receptor GFRα3 is expressed in a subpopulation of TRPM8 sensory neurons that have the neurochemical profile of cold nociceptors. Moreover, we found that artemin, the specific GFRα3 ligand that evokes heat hyperalgesia, robustly sensitized cold responses in a TRPM8-dependent manner in mice. In contrast, GFRα1 and GFRα2 are not coexpressed with TRPM8 and their respective ligands GDNF and neurturin did not induce cold pain, whereas they did evoke heat hyperalgesia. Nerve growth factor induced mild cold sensitization, consistent with TrkA expression in TRPM8 neurons. However, bradykinin failed to alter cold sensitivity even though its receptor expresses in a subset of TRPM8 neurons. These results show for the first time that only select neurotrophic factors induce cold sensitization through TRPM8 in vivo, unlike the broad range of proalgesic agents capable of promoting heat hyperalgesia.

Artemin, a Glial Cell Line-Derived Neurotrophic Factor Family Member, Induces TRPM8-Dependent Cold Pain