Articles: peripheral-nerve-injuries.
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Preclinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). ⋯ Transcriptional changes induced by Mef2c overexpression were different than those observed after desipramine treatment, suggesting a mechanism of action different from antidepressants. Overall, we show that interventions in MEF2C-regulated mechanisms in the NAc are sufficient to disrupt the maintenance of chronic pain states, providing potential new treatment avenues for neuropathic pain.
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There is a rich literature describing the loss of dorsal root ganglion (DRG) neurons following peripheral axotomy, but the vulnerability of discrete subpopulations has not yet been characterised. Furthermore, the extent or even presence of neuron loss following injury has recently been challenged. In this study, we have used a range of transgenic recombinase driver mouse lines to genetically label molecularly defined subpopulations of DRG neurons and track their survival following traumatic nerve injury. ⋯ We show that this subpopulation is almost entirely lost following spared nerve injury and severely depleted (by roughly 50%) following sciatic nerve crush. Finally, we used an in vitro model of DRG neuron survival to demonstrate that nonpeptidergic nociceptor loss is likely dependent on the absence of neurotrophic support. Together, these results profile the extent to which DRG neuron subpopulations can survive axotomy, with implications for our understanding of nerve injury-induced plasticity and pain.
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Yonsei medical journal · Dec 2024
A Novel Approach to Peripheral Nerve Regeneration: Local FK-506 Delivery Using a Reservoir Flap Model.
Peripheral nerve injuries can lead to lasting functional impairments, impacting movement and quality of life. FK-506, a widely used immunosuppressant, has demonstrated potential in promoting nerve regeneration in addition to its immunosuppressive effects. This study investigates the use of a local reservoir flap to deliver FK-506 directly to the nerve injury site, aiming to enhance nerve regeneration while minimizing systemic immunosuppression. ⋯ Localized FK-506 administration via a reservoir flap effectively enhances peripheral nerve regeneration and minimizes systemic immunosuppression, making it a promising approach for clinical application in treating peripheral nerve injuries.
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Focal nerve injuries are often associated with neuropathic pain. Preclinical research suggests altered neuroimmune signalling underlies such neuropathic pain; however, its cause remains poorly understood in humans. In this multicentre cohort study, we describe the local cellular and molecular signature of neuropathic pain at the lesion site, using Morton's neuroma as a human model system of neuropathic pain (n = 22; 18 women) compared with nerves from participants without nerve injury (n = 11; 4 women). ⋯ Targeted immunofluorescent analyses confirmed higher densities of intraneural CD163 + MARCO + macrophage subsets in Morton's neuroma. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans, with macrophages and specifically the M(GC) MARCO + subset implicated.