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.W hen pain continues past its usefulness as a warning of potential tissue damage, it becomes a debilitating condition for which few viable treatments are currently available. The result can be an exacerbation of pain in response to both innocuous (allodynia) and noxious (hyperalgesia) stimuli (1). For example, pain felt with normally pleasant mild cooling (cold allodynia) occurs in many pathological conditions, such as fibromyalgia, multiple sclerosis, stroke, and chemotherapeutic-induced polyneuropathy, but what underlies this specific form of pain at the cellular or molecular level is largely unknown (2-5). Pain-sensing afferent neurons (nociceptors) are sensitized during injury or disease, in part, by a vast array of proalgesic compounds termed the "inflammatory soup" (e.g., neurotrophic factors, protons, bradykinin, prostaglandins, and ATP) (1). These substances are released locally at the site of injury by infiltrating immune cells, such as macrophages, neutrophils, and T cells, as well as resident cells, including keratinocytes and mast cells (6), and either directly activate sensory receptors or sensitize them to subsequent stimuli (7). Moreover, prolonged inflammation can lead to central sensitization (in the spinal cord and brain) and bring about long-lasting chronic pain that persists after acute inflammation has resolved. Thus, a better understanding of the molecules involved in neuroinflammation may lead to therapeutic options for acute and chronic pain.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 (8-11). Both are major components of the inflammatory soup and produce nociceptor sensitization and pain through their cognate cell surface rece...

Regulation of Pain and Itch by TRP Channels

“…This concept was convincingly demonstrated using the evaporative cooling assay, where neurotrophic factors were injected into the foot-pad with subsequent application of acetone-evoked evaporative cooling to the paw. Wild-type mice showed an increase in cold-response with growth factors, while Trpm8 -/mice did not [182,183].…”

“…TRPM8 has been mechanistically linked to cold hypersensitivity [181]. Unlike heat hyperalgesia which is produced by several algogenic agents, TRPM8 cold sensitization appears to be evoked by neurotrophic factors such as artemin and nerve growth factor which produce their effects through specific receptors co-expressed with TRPM8 in a subset of sensory neurons [182,183]. This concept was convincingly demonstrated using the evaporative cooling assay, where neurotrophic factors were injected into the foot-pad with subsequent application of acetone-evoked evaporative cooling to the paw.…”

Correlation of Artemin and GFRα3 With Osteoarthritis Pain: Early Evidence From Naturally Occurring Osteoarthritis-Associated Chronic Pain in Dogs

“…The glial cell line-derived neurotrophic factor (GDNF) family members (GDNF, neurturin, and artemin) sensitize nociceptors; in particular, artemin is an important effector in inflammatory hyperalgesia (Malin et al, 2006). Artemin is thought to be an important endogenous mediator for inflammation, migraine, burning mouth syndrome, and neuropathic cold allodynia (Lippoldt et al, 2013(Lippoldt et al, , 2016Shinoda et al, 2015;Shang et al, 2016;Nencini et al, 2018). Recently, artemin signaling pathways have been shown to be involved in the pathogenesis of bone pain (Nencini et al, 2018).…”

“…GFRα1 and GFRα2 receptor expression has been demonstrated in the non-peptidergic neuronal populations, but, in contrast, GFRα3 is predominantly expressed by a subpopulation of nociceptive sensory neurons that are peptidergic (Orozco et al, 2001;Elitt et al, 2006), some or all of which also express the Ret receptor tyrosine kinase, and by the transient receptor potential (TRP) ion channel proteins TRPV1 and TRPA1 (Orozco et al, 2001;Elitt et al, 2006;Goswami et al, 2014). Furthermore, the GFRα3 receptor is also expressed by transient receptor potential cation channel subfamily melastatin (TRPM8) expressing neurons that are involved in encoding cold sensations (Lippoldt et al, 2013(Lippoldt et al, , 2016. Outside of the dorsal root ganglia (DRG), other reports suggest the expression of GFRα3 in non-neuronal cells (Yang et al, 2006;Thai et al, 2019).…”

(206) Modulation of multiple modalities of somatosensory information by peripheral kappa opioid receptors

“…Interestingly, though, a recent study from the McKemy lab found that GFRα3 KO mice showed selective reductions in cold allodynia in models of inflammatory, neuropathic, and chemotherapy-induced pain (CPN) (Lippoldt, Ongun, Kusaka, & McKemy, 2016). This lab has previously described artemin, …”