Common Antidepressant Shows Effectiveness in Treating Multiple Sclerosis-Related Neuropathic Pain in Animal Model

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MS-related neuropathic pain is due to hyperexcitability in the primary somatosensory cortex (green), and activation of the cingulate cortex (red)
MS-related neuropathic pain is due to hyperexcitability in the primary somatosensory cortex (green), and activation of the cingulate cortex (red)

Multiple sclerosis (MS) patients suffer from secondary symptoms, which include pain, 40% of which is of neuropathic origin.1,2 In the autoimmune encephalomyelitis (EAE) experimental model of MS, animals display pathobiology in common with humans, including demyelination, neurodegeneration and paralysis, but also neuroinflammation which was shown to contribute to sensory and cognitive disabilities as well as pain.3 In mice with EAE, thermal and mechanical allodynia preceded paralysis onset4, and hyper neuronal activation in the spinal cord dorsal horn.5

In a recent study published in the Journal of Neuroinflammation, researchers at the University of Alberta, Canada, sought to investigate changes in structure and neuronal activity in higher sensory cortex related to pain sensitivity in an EAE model.6 EAE in mice was induced by SC injection of myelin oligodendrocyte glycoprotein (50 µg) and emulsified Complete Freund's Adjuvant (CFA, 1.5 with heat-killed Myobacterium tuberculosis H37Ra followed by IP injections of pertussis toxin; control mice were injected with CFA/H37Ra and toxin. Allodynia which occurs in MS and the EAE model is associated with hyperexcitability in the primary somatosensory cortex (S1), leading to chronic pain  and activation of the cingulate cortex involved in pain processing.7

In vivo flavoprotein autofluorescence imaging (FAI) in S1 was used to assess neuronal responses to vibrotactile limb stimulation in the early phase of EAE. During the allodynia-only acute phase of EAE (preceding appearance of other symptoms), FAI responses were enhanced in EAE animals compared to controls in response to vibrotactile stimulation (one-way ANOVA, p = .012), and in a larger area (one-way ANOVA, p = .009). EAE animals had a prolonged time between FAI signal-peak and FAI signal-offset, underlying an overall increase in signal duration (one-way ANOVA, p = .013).

Immunohistochemical analyses revealed increased expression of vesicular glutamate transporter (VGLUT1) expression and reduced parvalbumin immunoreactivity in the perisomatic area of cortical layers 2/3 pyramidal neurons. Peri-neuronal nets, referring to extracellular matrix components surrounding parvalbumin-positive neurons which are essential to fast inhibitory activity and regulation of plasticity, were reduced in S1 of EAE animals (one-way ANOVA, p = .008). Excitatory S1 neurons also had increased number of spine densities and microglia in the acute disease stage.

The antidepressant phenelzine brought mechanical thresholds, FAI responses, spinal morphology, number of microglia and VGLUT1 reactivity to normal levels in EAE animals, but was ineffective in preserving peri-neuronal nets.

Authors concluded that, in the early phase of the disease, the excitatory-inhibitory balance of the somatosensory cortex is disrupted, in favor of hyper-excitation. The results also indicate that phenelzine might be effective in treating MS-related neuropathic pain.


1.O'connor AB, Schwid SR, Herrmann DN, Markman JD, Dworkin RH. Pain associated with multiple sclerosis: systematic review and proposed classification. Pain. 2008;137(1):96-111.

2.Watson JC, Sandroni P. Central Neuropathic Pain Syndromes. Mayo Clin Proc. 2016;91(3):372-85.

3.Musella A, Mandolesi G, Mori F, Gentile A, Centonze D. Linking synaptopathy and gray matter damage in multiple sclerosis. Mult Scler. 2016;22(2):146-9.

4.Olechowski CJ, Parmar A, Miller B, et al. A diminished response to formalin stimulation reveals a role for the glutamate transporters in the altered pain sensitivity of mice with experimental autoimmune encephalomyelitis (EAE). Pain. 2010;149(3):565-72.

5.Gao YJ, Ji RR. c-Fos and pERK, which is a better marker for neuronal activation and central sensitization after noxious stimulation and tissue injury?. Open Pain J. 2009;2:11-17.

6.Potter LE, Paylor JW, Suh JS, et al. Altered excitatory-inhibitory balance within somatosensory cortex is associated with enhanced plasticity and pain sensitivity in a mouse model of multiple sclerosis. J Neuroinflammation. 2016;13(1):142.

7.Eto K, Wake H, Watanabe M, et al. Inter-regional contribution of enhanced activity of the primary somatosensory cortex to the anterior cingulate cortex accelerates chronic pain behavior. J Neurosci. 2011;31(21):7631-6.


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