Related Experiment Video
Updated: Mar 19, 2026
Modified Spared Nerve Injury Surgery Model of Neuropathic Pain in Mice
Published on: January 25, 2022
Altered excitatory-inhibitory balance within somatosensory cortex is associated with enhanced plasticity and pain
Liam E Potter1,2, John W Paylor1,3, Jee Su Suh2
1Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada.
Background:
Chronic neuropathic pain is a common symptom of multiple sclerosis (MS). MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) has been used as an animal model to investigate the mechanisms of pain in MS. Previous studies have implicated sensitization of spinal nociceptive networks in the pathogenesis of pain in EAE. However, the involvement of supraspinal sites of nociceptive integration, such as the primary somatosensory cortex (S1), has not been defined. We therefore examined functional, structural, and immunological alterations in S1 during the early stages of EAE, when pain behaviors first appear. We also assessed the effects of the antidepressant phenelzine (PLZ) on S1 alterations and nociceptive (mechanical) sensitivity in early EAE. PLZ has been shown to restore central nervous system (CNS) tissue concentrations of GABA and the monoamines (5-HT, NA) in EAE. We hypothesized that PLZ treatment would also normalize nociceptive sensitivity in EAE by restoring the balance of excitation and inhibition (E-I) in the CNS.
Methods:
We used in vivo flavoprotein autofluorescence imaging (FAI) to assess neural ensemble responses in S1 to vibrotactile stimulation of the limbs in early EAE. We also used immunohistochemistry (IHC), and Golgi-Cox staining, to examine synaptic changes and neuroinflammation in S1. Mechanical sensitivity was assessed at the clinical onset of EAE with Von Frey hairs.
Results:
Mice with early EAE exhibited significantly intensified and expanded FAI responses in S1 compared to controls. IHC revealed increased vesicular glutamate transporter (VGLUT1) expression and disrupted parvalbumin+ (PV+) interneuron connectivity in S1 of EAE mice. Furthermore, peri-neuronal nets (PNNs) were significantly reduced in S1. Morphological analysis of excitatory neurons in S1 revealed increased dendritic spine densities. Iba-1+ cortical microglia were significantly elevated early in the disease. Chronic PLZ treatment was found to normalize mechanical thresholds in EAE. PLZ also normalized S1 FAI responses, neuronal morphologies, and cortical microglia numbers and attenuated VGLUT1 reactivity-but did not significantly attenuate the loss of PNNs.
Conclusions:
These findings implicate a pro-excitatory shift in the E-I balance of the somatosensory CNS, arising early in the pathogenesis EAE and leading to large-scale functional and structural plasticity in S1. They also suggest a novel antinociceptive effect of PLZ treatment.
Insights
Chronic neuropathic pain in multiple sclerosis (MS) involves changes in the brain's primary somatosensory cortex (S1). The antidepressant phenelzine (PLZ) normalized pain sensitivity and S1 function in an MS animal model by restoring neural balance.
Area of Science:
- Neuroscience
- Immunology
- Pain Research
Background:
- Chronic neuropathic pain is a significant symptom in multiple sclerosis (MS).
- The MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) model is used to study MS pain.
- Supraspinal pain integration sites, like the primary somatosensory cortex (S1), are understudied in MS pain.
Purpose of the Study:
- To investigate functional, structural, and immunological changes in S1 during early EAE.
- To assess the effects of phenelzine (PLZ) on S1 alterations and pain sensitivity in EAE.
- To determine if PLZ restores the excitation-inhibition (E-I) balance in the CNS.
Main Methods:
- In vivo flavoprotein autofluorescence imaging (FAI) to assess S1 neural activity.
- Immunohistochemistry (IHC) and Golgi-Cox staining for synaptic and neuroinflammatory changes.
- Behavioral testing using Von Frey hairs to measure mechanical sensitivity.
Main Results:
- Early EAE mice showed heightened S1 responses, increased VGLUT1, disrupted PV+ interneurons, reduced PNNs, and increased microglia.
- PLZ treatment normalized mechanical sensitivity, S1 activity, neuronal morphology, and microglia levels in EAE mice.
- PLZ attenuated VGLUT1 reactivity but did not restore PNNs.
Conclusions:
- A pro-excitatory shift in S1 contributes to early EAE pathogenesis and plasticity.
- PLZ exhibits a novel antinociceptive effect by normalizing S1 function and E-I balance.
