Dermal macrophages set pain sensitivity by modulating tissue NGF levels through SNX25–Nrf2 signaling

Abstract Crosstalk between peripheral neurons and immune cells plays important roles in pain sensation. We identified sorting nexin 25 (Snx25) as a pain-modulating gene in a transgenic mouse line with reduced pain behavior. Snx25 conditional-KO (cKO) in monocyte/macrophage-lineage cells but not in the peripheral sensory neurons reduced pain responses in both normal and neuropathic conditions. Cross transplantation experiments of bone marrows between cKO and wild type (WT) mice revealed that cKO macrophages caused dull phenotype in WT mice and WT macrophages in turn increased pain behavior in cKO mice. SNX25 in dermal macrophages enhances NGF (one of the key factors in pain sensation) production by inhibiting ubiquitin-mediated degradation of Nrf2, a transcription factor that activates Ngf mRNA synthesis. We conclude that dermal macrophages set pain sensitivity by producing and secreting NGF into the dermis in addition to their host defense functions.

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Dermal macrophages set pain sensitivity by modulating tissue NGF levels through SNX25–Nrf2 signaling

10.1101/2021.01.26.428327 ◽

2021 ◽

Author(s):

Tatsuhide Tanaka ◽

Hiroaki Okuda ◽

Yuki Terada ◽

Takeaki Shinjo ◽

Mitsuko Banja ◽

...

Keyword(s):

Pain Sensitivity ◽

Pain Behavior ◽

Mrna Synthesis ◽

Pain Sensation ◽

Key Factors ◽

Transgenic Mouse Line ◽

Sorting Nexin ◽

Peripheral Neurons ◽

Peripheral Sensory ◽

Transplantation Experiments

AbstractCrosstalk between peripheral neurons and immune cells plays important roles in pain sensation. We identified sorting nexin 25 (Snx25) as a pain-modulating gene in a transgenic mouse line with reduced pain behavior. Snx25 conditional-KO (cKO) in monocyte/macrophage-lineage cells but not in the peripheral sensory neurons reduced pain responses in both normal and neuropathic conditions. Cross transplantation experiments of bone marrows between cKO and wild type (WT) mice revealed that cKO macrophages caused dull phenotype in WT mice and WT macrophages in turn increased pain behavior in cKO mice. SNX25 in dermal macrophages enhances NGF (one of the key factors in pain sensation) production by inhibiting ubiquitin-mediated degradation of Nrf2, a transcription factor that activates Ngf mRNA synthesis. We conclude that dermal macrophages set pain sensitivity by producing and secreting NGF into the dermis in addition to their host defense functions.

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Mice lacking Kcns1 in peripheral neurons show increased basal and neuropathic pain sensitivity

Pain ◽

10.1097/j.pain.0000000000001255 ◽

2018 ◽

Vol 159 (8) ◽

pp. 1641-1651 ◽

Cited By ~ 6

Author(s):

Christoforos Tsantoulas ◽

Franziska Denk ◽

Massimo Signore ◽

Mohammed A. Nassar ◽

Kensuke Futai ◽

...

Keyword(s):

Neuropathic Pain ◽

Pain Sensitivity ◽

Peripheral Neurons

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Non-pharmacological methods of pain relief and systemic analgesia in labour

10.1093/med/9780198713333.003.0013 ◽

2016 ◽

Author(s):

Grace McClune ◽

David Hill

Keyword(s):

Pain Relief ◽

Complementary Therapies ◽

Healthcare Professionals ◽

Labour Pain ◽

Opioid Analgesia ◽

Sensory Receptors ◽

Pain Sensation ◽

Routes Of Administration ◽

Inhibitory Pathways ◽

Peripheral Sensory

Pain in labour is an issue common to women the world over. Healthcare professionals have an important role in helping women to understand this pain and to make informed choices regarding its management. Pain relief for labour comes in many forms. This chapter explores the theory behind labour pain and then discusses the use of non-pharmacological methods of pain relief (complementary therapies) or systemic analgesia in labour. The non-pharmacological methods described include those that aim to reduce painful stimuli and those that modulate pain sensation by the activation of peripheral sensory receptors or the enhancement of descending inhibitory pathways. Systemic analgesia in labour described in this chapter includes the use of inhalational agents, non-opioid analgesia, and opioid analgesia. The rationale behind the use of each method described is discussed along with evidence regarding the efficacy and limitations where available. Routes of administration and dosing are included where applicable. The potential for maternal or neonatal side effects is highlighted and conclusions drawn for each method as to the implications of the evidence to use in practice.

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VGLUTs in Peripheral Neurons and the Spinal Cord: Time for a Review

ISRN Neurology ◽

10.1155/2013/829753 ◽

2013 ◽

Vol 2013 ◽

pp. 1-28 ◽

Cited By ~ 23

Author(s):

Pablo R. Brumovsky

Keyword(s):

Spinal Cord ◽

Synaptic Vesicles ◽

Morphological Analysis ◽

Current Knowledge ◽

Historical Account ◽

Peripheral Neurons ◽

Physiological Relevance ◽

Autonomic Neurons ◽

Vesicular Glutamate Transporters ◽

Peripheral Sensory

Vesicular glutamate transporters (VGLUTs) are key molecules for the incorporation of glutamate in synaptic vesicles across the nervous system, and since their discovery in the early 1990s, research on these transporters has been intense and productive. This review will focus on several aspects of VGLUTs research on neurons in the periphery and the spinal cord. Firstly, it will begin with a historical account on the evolution of the morphological analysis of glutamatergic systems and the pivotal role played by the discovery of VGLUTs. Secondly, and in order to provide an appropriate framework, there will be a synthetic description of the neuroanatomy and neurochemistry of peripheral neurons and the spinal cord. This will be followed by a succinct description of the current knowledge on the expression of VGLUTs in peripheral sensory and autonomic neurons and neurons in the spinal cord. Finally, this review will address the modulation of VGLUTs expression after nerve and tissue insult, their physiological relevance in relation to sensation, pain, and neuroprotection, and their potential pharmacological usefulness.

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Pain behavior without pain sensation

Pain ◽

10.1097/j.pain.0000000000001741 ◽

2020 ◽

Vol 161 (3) ◽

pp. 502-508

Author(s):

Koichi Hagiwara ◽

Luis Garcia-Larrea ◽

Léon Tremblay ◽

Alexandra Montavont ◽

Hélène Catenoix ◽

...

Keyword(s):

Pain Behavior ◽

Pain Sensation

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Importin α3 regulates chronic pain pathways in peripheral sensory neurons

Science ◽

10.1126/science.aaz5875 ◽

2020 ◽

Vol 369 (6505) ◽

pp. 842-846 ◽

Cited By ~ 3

Author(s):

Letizia Marvaldi ◽

Nicolas Panayotis ◽

Stefanie Alber ◽

Shachar Y. Dagan ◽

Nataliya Okladnikov ◽

...

Keyword(s):

Neuropathic Pain ◽

Sensory Neurons ◽

Nuclear Import ◽

Nucleocytoplasmic Transport ◽

Dominant Negative ◽

Peripheral Neurons ◽

Pain Pathways ◽

Peripheral Sensory Neurons ◽

Control Pain ◽

Peripheral Sensory

How is neuropathic pain regulated in peripheral sensory neurons? Importins are key regulators of nucleocytoplasmic transport. In this study, we found that importin α3 (also known as karyopherin subunit alpha 4) can control pain responsiveness in peripheral sensory neurons in mice. Importin α3 knockout or sensory neuron–specific knockdown in mice reduced responsiveness to diverse noxious stimuli and increased tolerance to neuropathic pain. Importin α3–bound c-Fos and importin α3–deficient neurons were impaired in c-Fos nuclear import. Knockdown or dominant-negative inhibition of c-Fos or c-Jun in sensory neurons reduced neuropathic pain. In silico screens identified drugs that mimic importin α3 deficiency. These drugs attenuated neuropathic pain and reduced c-Fos nuclear localization. Thus, perturbing c-Fos nuclear import by importin α3 in peripheral neurons can promote analgesia.

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Control of mechanical pain hypersensitivity through ligand-targeted photoablation of TrkB positive sensory neurons

10.1101/233452 ◽

2017 ◽

Author(s):

Rahul Dhandapani ◽

Cynthia Mary Arokiaraj ◽

Francisco J. Taberner ◽

Paola Pacifico ◽

Sruthi Raja ◽

...

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Sensory Neurons ◽

Mechanical Allodynia ◽

List Type ◽

Light Touch ◽

Peripheral Neurons ◽

Necessary And Sufficient ◽

Peripheral Sensory

SummaryMechanical allodynia is a major symptom of neuropathic pain whereby innocuous touch evokes severe pain. Here we identify a population of peripheral sensory neurons expressing TrkB that are both necessary and sufficient for producing pain from light touch after nerve injury. Mice in which TrkB-Cre expressing neurons are ablated are less sensitive to the lightest touch under basal conditions, and fail to develop mechanical allodynia in a model of neuropathic pain. Moreover, selective optogenetic activation of these neurons after nerve injury evokes marked nociceptive behavior. Using a phototherapeutic approach based upon BDNF, the ligand for TrkB, we perform molecule-guided laser ablation of these neurons and achieve long-term retraction of TrkB positive neurons from the skin and pronounced reversal of mechanical allodynia across multiple types of neuropathic pain. Thus we identify the peripheral neurons which transmit pain from light touch and uncover a novel pharmacological strategy for its treatment.HighlightsTrkB+ neurons detect light touch under basal conditionsTrkB+ neurons convey mechanical allodynia in neuropathic pain statesA photosensitizing derivative of BDNF allows for photoablation of TrkB+ neuronsBDNF-guided photoablation reverses allodynia in multiple types of neuropathic pain

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XXI.—The Independence of Peripheral Sensory Neurons in view of the Results of Experimental Section of the Optic Nerve in the Rabbit

Proceedings of the Royal Society of Edinburgh ◽

10.1017/s0370164600025189 ◽

1912 ◽

Vol 31 ◽

pp. 349-351

Author(s):

Janie Hamilton McIlroy

Keyword(s):

Visual Cortex ◽

Optic Nerve ◽

Sensory Neurons ◽

Conduction Path ◽

Peripheral Neurons ◽

Experimental Section ◽

Peripheral Injury ◽

Series Of Experiments ◽

The Stability ◽

Peripheral Sensory

The problem of the amount of independence possessed by the units which go to make up the nervous system is one which has long occupied the attention of neuro-pathologists, and is still far from solved. That degenerative changes, as the result of peripheral injury, may extend across several intermediate neurons is indicated by the work of many investigators, notably v. Monakow, Campbell, Bolton, etc. Thus after enucleation of the eyeball changes have been met with in the visual cortex, showing that degeneration has travelled over the neurons situated at the basal ganglia of the cerebrum to the neurons in the visual cortex itself. Interruption of the sensory conduction path affects the integrity of themore centrally placed neurons. The question of the stability of the peripheral neurons under similar conditions has not received attention. Birch-Hirschfeld in 1900 published the results of a large series of experiments upon the retina, including a few cases of the effects of experimental section of the optic nerve.

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