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

Abstract

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 GFR␣3 is expressed in a subpopulation of TRPM8 sensory neurons that have the neurochemical profile of cold nociceptors. Moreover, we found that artemin, the specific GFR␣3 ligand that evokes heat hyperalgesia, robustly sensitized cold responses in a TRPM8-dependent manner in mice. In contrast, GFR␣1 and GFR␣2 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.

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

“…S5). TRPM8 is the principle cold thermoreceptor in mammals, and we have shown that it is required for artemin-mediated cold allodynia (8,31). GFRα3 is expressed in one-half of TRPM8 + DRG neurons (8), but consistent with our transcript expression analysis, we observed no difference in the number of TRPM8-positive neurons between WT and Gfrα3 −/− mice (Fig.…”

“…NGF, protons, bradykinin, and histamine, to name a few, are all capable of potentiating TRPV1 responses (7,29,44,45) and responsible for the development of heat hyperalgesia. However, only artemin and NGF induce cold allodynia in a manner similar to that found after injury (8). Here, Fig.…”

“…Previously, we showed that intraplantar hind paw injections of artemin or NGF induce a robust and transient TRPM8-dependent cold allodynia (8). The NGF/TrkA signaling pathways and their requirement in sensory neuron development and sensitization are well-established (1), but how GFRα receptors induce sensory neuron sensitization is poorly understood.…”

“…To date, unlike heat and mechanical hyperalgesia, only artemin and to a lesser extent, NGF have been found to induce cold hypersensitivity in mice when administered by intraplantar injections (8,9,11). NGF signals through the tyrosine kinase TrkA and is a major mediator of heat hyperalgesia through sensitization of the heat-gated capsaicin receptor TRPV1 (36,37).…”

“…Of the range of proalgesics known to promote pain, only nerve growth factor (NGF) and the glial cell line-derived neurotrophic factor family ligand (GFL) artemin have been shown to lead to cold hypersensitivity (8)(9)(10)(11). Both are major components of the inflammatory soup and produce nociceptor sensitization and pain through their cognate cell surface receptors.…”