title: Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3.
abstract: Tissue injury prompts the release of a number of proalgesic molecules that induce acute and chronic pain by sensitizing pain-sensing neurons (nociceptors) to heat and mechanical stimuli. In contrast, many proalgesics have no effect on cold sensitivity or can inhibit cold-sensitive neurons and diminish cooling-mediated pain relief (analgesia). Nonetheless, cold pain (allodynia) is prevalent in many inflammatory and neuropathic pain settings, with little known of the mechanisms promoting pain vs. those dampening analgesia. Here, we show that cold allodynia induced by inflammation, nerve injury, and chemotherapeutics is abolished in mice lacking the neurotrophic factor receptor glial cell line-derived neurotrophic factor family of receptors-α3 (GFRα3). Furthermore, established cold allodynia is blocked in animals treated with neutralizing antibodies against the GFRα3 ligand, artemin. In contrast, heat and mechanical pain are unchanged, and results show that, in striking contrast to the redundant mechanisms sensitizing other modalities after an insult, cold allodynia is mediated exclusively by a single molecular pathway, suggesting that artemin-GFRα3 signaling can be targeted to selectively treat cold pain.
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089;
authors.forename: Erika K
authors.initials: EK
authors.lastname: Lippoldt
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Molecular and Computational Biology Graduate Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089.
authors.forename: Serra
authors.initials: S
authors.lastname: Ongun
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089;
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Kusaka
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Molecular and Computational Biology Graduate Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089 mckemy@usc.edu.
authors.forename: David D
authors.initials: DD
authors.lastname: McKemy
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D004195:Disease Models, Animal; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010146:Pain / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D057134:Antibodies, Neutralizing; C116599:Artn protein, mouse; C494994:Gfra3 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009419:Nerve Tissue Proteins
keywords: Gfrα3; allodynia; artemin; cold; pain