Abstract
BackgroundPeripheral nerve injury can have long-term consequences including pain-related manifestations, such as hypersensitivity to cutaneous stimuli, as well as affective and cognitive disturbances, suggesting the involvement of supraspinal mechanisms. Changes in brain structure and cortical function associated with many chronic pain conditions have been reported in the prefrontal cortex (PFC). The PFC is implicated in pain-related co-morbidities such as depression, anxiety and impaired emotional decision-making ability. We recently reported that this region is subject to significant epigenetic reprogramming following peripheral nerve injury, and normalization of pain-related structural, functional and epigenetic abnormalities in the PFC are all associated with effective pain reduction.In this study, we used the Spared Nerve Injury (SNI) model of neuropathic pain to test the hypothesis that peripheral nerve injury triggers persistent long-lasting changes in gene expression in the PFC, which alter functional gene networks, thus providing a possible explanation for chronic pain associated behaviors.ResultsSNI or sham surgery where performed in male CD1 mice at three months of age. Six months after injury, we performed transcriptome-wide sequencing (RNAseq), which revealed 1147 differentially regulated transcripts in the PFC in nerve-injured vs. control mice. Changes in gene expression occurred across a number of functional gene clusters encoding cardinal biological processes as revealed by Ingenuity Pathway Analysis. Significantly altered biological processes included neurological disease, skeletal muscular disorders, behavior, and psychological disorders. Several of the changes detected by RNAseq were validated by RT-QPCR and included transcripts with known roles in chronic pain and/or neuronal plasticity including the NMDA receptor (glutamate receptor, ionotropic, NMDA; grin1), neurite outgrowth (roundabout 3; robo3), gliosis (glial fibrillary acidic protein; gfap), vesicular release (synaptotagmin 2; syt2), and neuronal excitability (voltage-gated sodium channel, type I; scn1a).ConclusionsThis study used an unbiased approach to document long-term alterations in gene expression in the brain following peripheral nerve injury. We propose that these changes are maintained as a memory of an insult that is temporally and spatially distant from the initial injury.
Highlights
Peripheral nerve injury can have long-term consequences including pain-related manifestations, such as hypersensitivity to cutaneous stimuli, as well as affective and cognitive disturbances, suggesting the involvement of supraspinal mechanisms
Peripheral injury is accompanied by behavioral signs of neuropathic pain six months post-injury The persistence of nerve injury-induced hypersensitivity to mechanical and cold stimuli and injury-related motor impairment were confirmed six months following Spared Nerve Injury (SNI) (data not shown; mechanical thresholds = 0.20±0.05 in SNI vs 0.82±0.07 in controls, p0.0001; motor impairment = 76±11 in SNI vs. 225±21 in controls, p>0.0001; n=10/group)
The use of RNA sequencing (RNAseq) allowed for an unbiased picture of the transcriptomic changes involved in chronic neuropathy in the prefrontal cortex (PFC)
Summary
Peripheral nerve injury can have long-term consequences including pain-related manifestations, such as hypersensitivity to cutaneous stimuli, as well as affective and cognitive disturbances, suggesting the involvement of supraspinal mechanisms. We recently reported that this region is subject to significant epigenetic reprogramming following peripheral nerve injury, and normalization of pain-related structural, functional and epigenetic abnormalities in the PFC are all associated with effective pain reduction. Peripheral nerve injury can result in a multitude of changes within an organism, including motor dysfunction, pain and associated cognitive and emotional comorbidities. Occasionally the “memory” of injury, in the form of chronic pain, persists long after the initial recovery phase and becomes difficult to reverse. This is due, in part, to changes in anatomy and function that take place in the peripheral as well as the central nervous system. The full profile of transcriptional changes that accompany chronic pain in response to peripheral injury is unknown
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