New insights on the molecular mechanisms of collateral sprouting 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 Unpublished data further link SorCS2, another member of the Sortilins family of sorting receptors (sortilin, SorLA and SorCS1–3) to BDNF signaling by regulating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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(256) Molecular mechanisms of stress exacerbated neuropathic pain in peripheral nerve injury

Journal of Pain ◽

10.1016/j.jpain.2015.01.173 ◽

2015 ◽

Vol 16 (4) ◽

pp. S40

Author(s):

J. Lerch ◽

N. Hashi ◽

A. Zawerton ◽

T. Quach ◽

P. Popovich

Keyword(s):

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Molecular Mechanisms

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Sex-related difference in collateral sprouting of nociceptive axons after peripheral nerve injury in the rat

Experimental Neurology ◽

10.1016/s0014-4886(03)00269-3 ◽

2003 ◽

Vol 184 (1) ◽

pp. 479-488 ◽

Cited By ~ 34

Author(s):

U Kovac̆ic̆ ◽

J Sketelj ◽

F.F Bajrović

Keyword(s):

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Collateral Sprouting ◽

Related Difference

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The voltage-gated proton channel Hv1 promotes microglia-astrocyte communication and neuropathic pain after peripheral nerve injury

Molecular Brain ◽

10.1186/s13041-021-00812-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Jiyun Peng ◽

Min-Hee Yi ◽

Heejin Jeong ◽

Przemyslaw Peter McEwan ◽

Jiaying Zheng ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Molecular Mechanisms ◽

Proton Channel ◽

Astrocyte Activation ◽

Voltage Gated ◽

Ifn Γ

AbstractActivation of spinal cord microglia contributes to the development of peripheral nerve injury-induced neuropathic pain. However, the molecular mechanisms underlying microglial function in neuropathic pain are not fully understood. We identified that the voltage-gated proton channel Hv1, which is functionally expressed in spinal microglia, was significantly increased after spinal nerve transection (SNT). Hv1 mediated voltage-gated proton currents in spinal microglia and mice lacking Hv1 (Hv1 KO) display attenuated pain hypersensitivities after SNT compared with wildtype (WT) mice. In addition, microglial production of reactive oxygen species (ROS) and subsequent astrocyte activation in the spinal cord was reduced in Hv1 KO mice after SNT. Cytokine screening and immunostaining further revealed that IFN-γ expression was compromised in spinal astrocytes in Hv1 KO mice. These results demonstrate that Hv1 proton channel contributes to microglial ROS production, astrocyte activation, IFN-γ upregulation, and subsequent pain hypersensitivities after SNT. This study suggests Hv1-dependent microglia-astrocyte communication in pain hypersensitivities and identifies Hv1 as a novel therapeutic target for alleviating neuropathic pain.

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The Mechanisms of Peripheral Nerve Preconditioning Injury on Promoting Axonal Regeneration

Neural Plasticity ◽

10.1155/2021/6648004 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Xiaoyan Yang ◽

Ruixuan Liu ◽

Ying Xu ◽

XiangYu Ma ◽

Bing Zhou

Keyword(s):

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Axonal Regeneration ◽

Molecular Mechanisms ◽

Lipid Synthesis ◽

Nerve Lesion ◽

Axonal Regrowth ◽

Cord Injury ◽

Major Factors

Two major factors contribute to the failure of axonal regrowth in the central nervous system (CNS), namely, the neuronal intrinsic regenerative capacity and the extrinsic local inhibitory microenvironments. However, a preconditioning peripheral nerve lesion could substantially enhance the regeneration of central axons following a subsequent spinal cord injury. In the present review, we summarize the molecular mechanisms of the preconditioning injury effect on promoting axonal regeneration. The injury signal transduction resulting from preconditioning peripheral nerve injury regulates the RAG expression to enhance axonal regeneration. Importantly, preconditioning peripheral nerve injury triggers interactions between neurons and nonneuronal cells to amplify and maintain their effects. Additionally, the preconditioning injury impacts mitochondria, protein, and lipid synthesis. All these coordinated changes endow axonal regeneration.

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Therapeutic Low-Intensity Ultrasound for Peripheral Nerve Regeneration – A Schwann Cell Perspective

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.812588 ◽

2022 ◽

Vol 15 ◽

Author(s):

Jenica Acheta ◽

Shannon B. Z. Stephens ◽

Sophie Belin ◽

Yannick Poitelon

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Schwann Cells ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Molecular Mechanisms ◽

Peripheral Nerve Regeneration ◽

Small Population ◽

Low Intensity ◽

Low Intensity Ultrasound

Peripheral nerve injuries are common conditions that can arise from trauma (e.g., compression, severance) and can lead to neuropathic pain as well as motor and sensory deficits. Although much knowledge exists on the mechanisms of injury and nerve regeneration, treatments that ensure functional recovery following peripheral nerve injury are limited. Schwann cells, the supporting glial cells in peripheral nerves, orchestrate the response to nerve injury, by converting to a “repair” phenotype. However, nerve regeneration is often suboptimal in humans as the repair Schwann cells do not sustain their repair phenotype long enough to support the prolonged regeneration times required for successful nerve regrowth. Thus, numerous strategies are currently focused on promoting and extending the Schwann cells repair phenotype. Low-intensity ultrasound (LIU) is a non-destructive therapeutic approach which has been shown to facilitate peripheral nerve regeneration following nerve injury in rodents. Still, clinical trials in humans are scarce and limited to small population sizes. The benefit of LIU on nerve regeneration could possibly be mediated through the repair Schwann cells. In this review, we discuss the known and possible molecular mechanisms activated in response to LIU in repair Schwann cells to draw support and attention to LIU as a compelling regenerative treatment for peripheral nerve injury.

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