Inhibition of Endogenous NGF Degradation Induces Mechanical Allodynia and Thermal Hyperalgesia in Rats

Osikowicz, Maria; Longo, Geraldine; Allard, S.T.M.; Cuello, A. Claudio; Ribeiro‐da‐Silva, Alfredo

doi:10.1186/1744-8069-9-37

Cited by 14 publications

(14 citation statements)

References 88 publications

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“…What is a remarkable and seminal result of our study is that injury-induced cold allodynia of multiple etiologies is totally dependent on GFRα3, unlike the redundant nature of heat and mechanical pain that signal through a diverse repertoire of cell surface receptors (1). 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).…”

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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“…Because inhibition of mature NGF degradation in the skin induces sensory fiber sprouting and significantly decreases sensory thresholds, as previously demonstrated, 54 we used an anti-NGF antibody (mouse, 1:200; Santa Cruz, Dallas, TX, overnight) that recognizes its mature form. Alexa 488 anti-mouse secondary antibody (1:200; Invitrogen, Carlsbad, CA, 1 hour) was used for this labeling.…”

Section: Immunohistochemistry Of Paw Skinmentioning

confidence: 98%

Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury

López-Alvarez

Mòdol²,

Navarro³

et al. 2015

Pain

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Activity treatments, such as treadmill exercise, are used to improve functional recovery after nerve injury, parallel to an increase in neurotrophin levels. However, despite their role in neuronal survival and regeneration, neurotrophins may cause neuronal hyperexcitability that triggers neuropathic pain. In this work, we demonstrate that an early increasing-intensity treadmill exercise (iTR), performed during the first week (iTR1) or during the first 2 weeks (iTR2) after section and suture repair of the rat sciatic nerve, significantly reduced the hyperalgesia developing rapidly in the saphenous nerve territory and later in the sciatic nerve territory after regeneration. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in sensory neurons and spinal cord was reduced in parallel. iTR prevented the extension of collateral sprouts of saphenous nociceptive calcitonin gene-related peptide fibers within the adjacent denervated skin and reduced NGF expression in the same skin and in the L3 dorsal root ganglia (DRG). Injury also induced Na⁺-K⁺-2Cl⁻ cotransporter 1 (NKCC1) upregulation in DRG, and K⁺-Cl⁻ cotransporter 2 (KCC2) downregulation in lumbar spinal cord dorsal horn. iTR normalized NKCC1 and boosted KCC2 expression, together with a significant reduction of microgliosis in L3-L5 dorsal horn, and a reduction of BDNF expression in microglia at 1 to 2 weeks postinjury. These data demonstrate that specific activity protocols, such as iTR, can modulate neurotrophins expression after peripheral nerve injury and prevent neuropathic pain by blocking early mechanisms of sensitization such as collateral sprouting and NKCC1/KCC2 disregulation.

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“…In addition to K ATP channel subunits, NGF expression was elevated around injured tissues. Enhanced NGF is associated with inflammatory pain due to arthritis [7], so post-SMIR allodynia may involve peripheral inflammation, changes in afferent nerve excitability, and revascularization as well as reactive responses in the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, SMIR can lead to mechanical sensitization (allodynia) [7]. The pathogenesis of pain sensitization is multimodal, but appears to involve inflammatory processes.…”

Section: Introductionmentioning

confidence: 99%

Effect of adenosine triphosphate-sensitive potassium activation on peripheral and central pain sensitization

Shen

Cao

Huang

et al. 2015

Journal of Surgical Research

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Inhibition of Endogenous NGF Degradation Induces Mechanical Allodynia and Thermal Hyperalgesia in Rats

Cited by 14 publications

References 88 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

Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury

Effect of adenosine triphosphate-sensitive potassium activation on peripheral and central pain sensitization

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