SOCS3-Mediated Blockade of JAK/STAT3 Signaling Pathway Reveals Its Major Contribution to Spinal Cord Neuroinflammation and Mechanical Allodynia after Peripheral Nerve Injury

AbstractBackground/aimsThe molecular mechanisms underlying neuropathic pain are incompletely understood, but recent data suggest that down-regulation of the chloride extruding co-transporter KCC2 in spinal cord sensory neurons is critical: Following peripheral nerve injury, activated microglia in the spinal cord release BDNF, which stimulates neuronal TrkB receptors and ultimately results in the reduction of KCC2 levels. Consequently, neuronal intracellular chloride ion concentration increases, impairing GABAA-receptor mediated inhibition. We have previously described how the receptor sortilin modulates neurotrophin signaling by facilitating anterograde transport of Trk receptors. Unpublished data further link SorCS2, another member of the Sortilins family of sorting receptors (sortilin, SorLA and SorCS1–3) to BDNF signaling by regulating presynaptic TrkB trafficking. The purpose of this study is to explore the involvement of Sortilins in neuropathic pain.MethodsWe subjected wild-type (wt), sortilin knockout (Sort1-/-) and SorCS2 knockout (SorCS2-/-) mice to the Spared Nerve Injury (SNI) model of peripheral nerve injury. Mechanical allodynia was measured by von Frey filaments using the up-down-up method and a 3-out-of-5 thresshold.ResultsAs previously described by several groups, wt mice developed significant mechanical allodynia following SNI. Interestingly however, mice lacking sortilin or SorCS2 were fully protected from development of allodynia and did not display KCC2 down-regulation following injury. In addition, a single intrathecal injection of antibodies against sortilin or SorCS2 could delay or rescue mechanical allodynia in wt SNI mice for 2-3 days. Finally, neither sortilin nor SorCS2 deficient mice responded to intrathecal injection of BDNF, in contrast to wt mice which developed transient mechanical allodynia.ConclusionWe hypothesize that sortilin and SorCS2 are involved in neuropathic pain development by regulating TrkB signaling. Alternatively, Sortilins may directly influence the regulation of KCC2 membrane levels following injury. Both hypotheses are currently being investigated by our group.

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Graded peripheral nerve injury creates mechanical allodynia proportional to the progression and severity of microglial activity within the spinal cord of male mice

Brain Behavior and Immunity ◽

10.1016/j.bbi.2020.11.018 ◽

2021 ◽

Vol 91 ◽

pp. 568-577

Author(s):

Vasiliki Staikopoulos ◽

Sha Qiao ◽

Jiajun Liu ◽

Xianlin Song ◽

Xiaoquan Yang ◽

...

Keyword(s):

Spinal Cord ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Mechanical Allodynia ◽

Male Mice

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An Obligatory Role for Spinal Cholinergic Neurons in the Antiallodynic Effects of Clonidine after Peripheral Nerve Injury

Anesthesiology ◽

10.1097/00000542-200106000-00023 ◽

2001 ◽

Vol 94 (6) ◽

pp. 1074-1081 ◽

Cited By ~ 12

Author(s):

Xavier Paqueron ◽

Xinhui Li ◽

Carsten Bantel ◽

Joseph R. Tobin ◽

Mary Lou Voytko ◽

...

Keyword(s):

Spinal Cord ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Mechanical Allodynia ◽

Intrathecal Injection ◽

Cholinergic Neurons ◽

Receptor Expression ◽

Acetylcholine Content

Background Indirect evidence supports a role of spinal cholinergic neurons in tonically reducing response to noxious mechanical stimulation and in effecting analgesia from alpha2-adrenergic agonists. This study directly assessed the role of cholinergic neurons in regulating the level of mechanical allodynia and in participating in the antiallodynic effect of the clinically used alpha2-adrenergic agonist, clonidine, in an animal model of neuropathic pain. Methods Allodynia was produced in rats by ligation of the left L5 and L6 spinal nerves. Rats received a single intrathecal injection of saline or one of three different doses of the cholinergic neurotoxin, ethylcholine mustard aziridinium ion (AF64-A; 2, 5, and 15 nmol). Seven days later, allodynia was assessed before and after intrathecal injection of 15 microg clonidine. The spinal cord was removed, and spinal cord acetylcholine content, cholinergic neuron number and distribution, and alpha2-adrenergic receptor expression were determined. Results AF64-A administration reduced both the number of cholinergic cells and the acetylcholine content of the lumbar dorsal spinal cord by 20-50% but did not affect level of mechanical allodynia. AF64-A did, however, completely block the anti-allodynic effect of clonidine. AF64-A did not reduce alpha2-adrenergic ligand binding in dorsal lumbar cord. Conclusions These data suggest that spinal cholinergic tone does not affect the level of mechanical allodynia after peripheral nerve injury. There is a quantitative reliance on spinal cholinergic neurons in the allodynia relieving properties of intrathecal clonidine, and this reliance does not depend on alpha2-adrenergic receptors colocalized on spinal cholinergic interneurons.

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Spinal cord homeostatic plasticity gates mechanical allodynia in chronic pain

10.1101/2022.01.10.475704 ◽

2022 ◽

Author(s):

Bing Cao ◽

Gregory Scherrer ◽

Lu Chen

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Synaptic Plasticity ◽

Peripheral Nerve ◽

Nerve Injury ◽

Central Sensitization ◽

Peripheral Nerve Injury ◽

Mechanical Allodynia ◽

Homeostatic Plasticity ◽

Homeostatic Synaptic Plasticity

Central sensitization caused by disinhibition of spinal cord circuits is a key mechanism of mechanical allodynia in neuropathic pain. Despite intense efforts, the molecular mechanisms that drive disinhibition and induce allodynia after peripheral nerve injury remain unclear. Using the spared-nerve injury (SNI) model of allodynia, we here demonstrate that SNI induces disinhibition of spinal nociceptive circuits by triggering homeostatic synaptic plasticity. Specifically, SNI-triggered homeostatic plasticity suppresses the inhibitory outputs of parvalbumin-positive (PV+) interneurons that form synapses on both primary afferent terminals and excitatory interneurons, causing hyperactivation of the nociceptive pathway. Using genetic manipulations, we identified the retinoic acid receptor RARα as the key mediator of the homeostatic synaptic plasticity underlying this synaptic disinhibition. Deletion of RARα in PV+ neurons blocked SNI-induced spinal disinhibition, central sensitization, and allodynia. Moreover, deletion of RARα in spinal PV+ neurons or application of an RARα antagonist in the spinal cord prevented the development of SNI-induced mechanical allodynia. Together, our results reveal a molecular mechanism of neuropathic pain whereby homeostatic plasticity causes the mis-direction of tactile information flow to ascending nociceptive pathways following peripheral nerve injury.

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Transplantation Strategies for Spinal Cord Injury Based on Microenvironment Modulation

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200421112622 ◽

2020 ◽

Vol 15 (6) ◽

pp. 522-530

Author(s):

Jiawei Shu ◽

Feng Cheng ◽

Zhe Gong ◽

Liwei Ying ◽

Chenggui Wang ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Peripheral Nerve ◽

Nerve Injury ◽

Autonomic Dysfunction ◽

Peripheral Nerve Injury ◽

Therapeutic Effects ◽

Permanent Damage ◽

Cord Injury ◽

Severe Motor

Spinal cord injury (SCI) is different from peripheral nerve injury; it results in devastating and permanent damage to the spine, leading to severe motor, sensory and autonomic dysfunction. SCI produces a complex microenvironment that can result in hemorrhage, inflammation and scar formation. Not only does it significantly limit regeneration, but it also challenges a multitude of transplantation strategies. In order to promote regeneration, researchers have recently begun to focus their attention on strategies that manipulate the complicated microenvironment produced by SCI. And some have achieved great therapeutic effects. Hence, reconstructing an appropriate microenvironment after transplantation could be a potential therapeutic solution for SCI. In this review, first, we aim to summarize the influential compositions of the microenvironment and their different effects on regeneration. Second, we highlight recent research that used various transplantation strategies to modulate different microenvironments produced by SCI in order to improve regeneration. Finally, we discuss future transplantation strategies regarding SCI.

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Transplantation of Embryonic Spinal Cord Derived Cells Helps to Prevent Muscle Atrophy after Peripheral Nerve Injury

International Journal of Molecular Sciences ◽

10.3390/ijms18030511 ◽

2017 ◽

Vol 18 (3) ◽

pp. 511 ◽

Cited By ~ 11

Author(s):

Carolin Ruven ◽

Wen Li ◽

Heng Li ◽

Wai-Man Wong ◽

Wutian Wu

Keyword(s):

Spinal Cord ◽

Peripheral Nerve ◽

Nerve Injury ◽

Muscle Atrophy ◽

Peripheral Nerve Injury ◽

Embryonic Spinal Cord

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SUR1, newly expressed in astrocytes, mediates neuropathic pain in a mouse model of peripheral nerve injury

Molecular Pain ◽

10.1177/17448069211006603 ◽

2021 ◽

Vol 17 ◽

pp. 174480692110066

Author(s):

Orest Tsymbalyuk ◽

Volodymyr Gerzanich ◽

Aaida Mumtaz ◽

Sanketh Andhavarapu ◽

Svetlana Ivanova ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Dorsal Horn ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Thermal Sensitivity ◽

Gradual Improvement ◽

Pain Behaviors

Background Neuropathic pain following peripheral nerve injury (PNI) is linked to neuroinflammation in the spinal cord marked by astrocyte activation and upregulation of interleukin 6 (IL -6 ), chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 1 (CXCL1), with inhibition of each individually being beneficial in pain models. Methods Wild type (WT) mice and mice with global or pGfap-cre- or pGFAP-cre/ERT2-driven Abcc8/SUR1 deletion or global Trpm4 deletion underwent unilateral sciatic nerve cuffing. WT mice received prophylactic (starting on post-operative day [pod]-0) or therapeutic (starting on pod-21) administration of the SUR1 antagonist, glibenclamide (10 µg IP) daily. We measured mechanical and thermal sensitivity using von Frey filaments and an automated Hargreaves method. Spinal cord tissues were evaluated for SUR1-TRPM4, IL-6, CCL2 and CXCL1. Results Sciatic nerve cuffing in WT mice resulted in pain behaviors (mechanical allodynia, thermal hyperalgesia) and newly upregulated SUR1-TRPM4 in dorsal horn astrocytes. Global and pGfap-cre-driven Abcc8 deletion and global Trpm4 deletion prevented development of pain behaviors. In mice with Abcc8 deletion regulated by pGFAP-cre/ERT2, after pain behaviors were established, delayed silencing of Abcc8 by tamoxifen resulted in gradual improvement over the next 14 days. After PNI, leakage of the blood-spinal barrier allowed entry of glibenclamide into the affected dorsal horn. Daily repeated administration of glibenclamide, both prophylactically and after allodynia was established, prevented or reduced allodynia. The salutary effects of glibenclamide on pain behaviors correlated with reduced expression of IL-6, CCL2 and CXCL1 by dorsal horn astrocytes. Conclusion SUR1-TRPM4 may represent a novel non-addicting target for neuropathic pain.

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