Sensitization of Cutaneous Nociceptors after Nerve Transection and Regeneration: Possible Role of Target-Derived Neurotrophic Factor Signaling

Jankowski, Michael P.; Lawson, Jeffrey J.; McIlwrath, Sabrina L.; Rau, Kristofer K.; Anderson, Collene E.; Albers, Kathryn M.; Koerber, H. Richard

doi:10.1523/jneurosci.3474-08.2009

Cited by 72 publications

(159 citation statements)

References 78 publications

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“…Similarly, GFLs potentiate capsaicin responses in dissociated DRG neurons recorded by Ca 2+ imaging, showing sensitization of TRPV1 + cells (45). However, specific changes in TRPV1 channel activity have not been reported, and the preponderance of data suggests that artemin-induced heat hyperalgesia is caused by increased TRPV1 expression (27,28,46,47). Moreover, unlike the established TRPM8 dependence of arteminand NGF-evoked cold allodynia (8) or the necessity of TRPV1 for NGF-induced heat hyperalgesia (36), the molecule determinants of GFL-evoked alterations in nociception in vivo are unknown (48).…”

Section: Discussionmentioning

confidence: 99%

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

Lippoldt

Ongun

Kusaka

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionmentioning

confidence: 99%

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

Lippoldt

Ongun

Kusaka

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Conversely, both P2Y 1 and P2Y 2 mRNAs are upregulated in mouse L2/L3 DRG cells at 14 and 21 days after nerve transection [53]. The upregulation of P2Y 1 mRNA in mouse DRGs appears to be necessary for heat sensitization of cutaneous polymodal nociceptors in response to CFA injection in the skin [54].…”

Section: Modulation Of Pain Transmission By P2y Receptors In Sensory mentioning

confidence: 92%

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

Magni

Ceruti

2013

Biochemical Pharmacology

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Non-standard abbreviations:AR-C126313, 5-(7-chloro-4H-1-thia-3-aza-benzo[f]-4-yl)-3-methyl-6-thioxo-piperadin-2-one; AR-C67085, [[[[(2R,3S,4R,5R)-5-(6-amino-2-propylsulfanylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]-dichloromethyl]phosphonic acid; AR-C69931MX, [dichloro-[[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-methylsulfanylethylamino)-2-(3,3,3-trifluoropropylsulfanyl) 3-[7-[[2-(3,4-BDNF, brain-derived neurotrophic factor; BK, bradykinin; CFA, Complete Freund's adjuvant; CGRP, calcitonin gene-related peptide; DRG, dorsal root ganglia; FHM1, familial hemiplegic migraine type 1; INS37217, P(1)-(uridine 5')-P(4)-(2'-deoxycytidine 5')tetraphosphate, tetrasodium salt; INS48823, {[(3aR,4R,6R,6aR)-2-benzyl-6-(2,4-dioxo-

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“…To confirm that STAT3 is activated after a PNS lesion, we studied the expression of STAT3 and its active, phosphorylated form P-STAT3 in DRG neurons by immunohistochemistry at different time points after creation of bilateral lesions of the saphenous nerves, which contain the axons of the third lumbar (L3) DRGs (26). Starting within a few hours and lasting for weeks after transection, we observed a significant increase in the number of P-STAT3-positive nuclei in L3 DRG neurons ( Fig.…”

Section: Stat3mentioning

confidence: 99%

In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration

Bareyre

Garzorz

Lang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

192

177

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In the peripheral nervous system (PNS), damaged axons regenerate successfully, whereas axons in the CNS fail to regrow. In neurons of the dorsal root ganglia (DRG), which extend branches to both the PNS and CNS, only a PNS lesion but not a CNS lesion induces axonal growth. How this differential growth response is regulated in vivo is only incompletely understood. Here, we combine in vivo timelapse fluorescence microscopy with genetic manipulations in mice to reveal how the transcription factor STAT3 regulates axonal regeneration. We show that selective deletion of STAT3 in DRG neurons of STAT3-floxed mice impairs regeneration of peripheral DRG branches after a nerve cut. Further, overexpression of STAT3 induced by viral gene transfer increases outgrowth and collateral sprouting of central DRG branches after a dorsal column lesion by more than 400%. Notably, repetitive in vivo imaging of individual fluorescently labeled PNS and CNS axons reveals that STAT3 selectively regulates initiation but not later perpetuation of axonal growth. With STAT3, we thus identify a phase-specific regulator of axonal outgrowth. Activating STAT3 might provide an opportunity to "jumpstart" regeneration, and thus prime axons in the injured spinal cord for application of complementary therapies that improve axonal elongation.in vivo microscopy | spinal cord injury | peripheral nerve lesion | intrinsic growth program L esioned peripheral nervous system (PNS) axons regenerate successfully, whereas lesioned CNS axons fail to regrow. This differential behavior is exemplified by neurons located in the dorsal root ganglia (DRG), which extend one branch into the PNS and another into the CNS. In these neurons, a cut in the PNS but not in the CNS is followed by neuronal outgrowth (1). If, however, the DRG neuron is "conditioned" by a transection of its peripheral branch, a subsequent central lesion can be followed by extensive outgrowth (2,3). This suggests the existence of a common intrinsic neuronal growth program that can, in principle, support both PNS and CNS growth but is normally initiated only after a PNS lesion. In recent years, several intracellular components that might regulate this intrinsic growth program have been identified (4, 5). They include a number of transcriptional regulators such as the transcription factors cJun (6), SMAD1 (7), ATF3 (8), AKRD1 (9), NFIL3 (10), and several KLF family members (11). One particularly interesting transcriptional regulator is STAT3, which is activated as part of the JAK-STAT signaling pathway (12). The following findings make STAT3 a good candidate for regulating axon growth: first, increased levels of STAT3 expression and phosphorylation are associated with axonal regeneration (13-15) and axonal remodelling (16). Second, molecules that can affect STAT3 signaling such as the neuropoietic cytokines IL-6, ciliary neurotrophic factor, and leukemia inhibitory factor, as well as the intracellular regulator SOCS3, have been shown to influence axonal regeneration (17-20). Third, STAT3 expression prom...

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Sensitization of Cutaneous Nociceptors after Nerve Transection and Regeneration: Possible Role of Target-Derived Neurotrophic Factor Signaling

Cited by 72 publications

References 78 publications

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

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

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration

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