Abstract
BackgroundChronic 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.MethodsWe 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.ResultsMice 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0609-4) contains supplementary material, which is available to authorized users.
Highlights
Chronic neuropathic pain is a common symptom of multiple sclerosis (MS)
The area of cortical activation elicited by this stimulus was significantly larger in the EAE group compared to naïve animals or mice treated with complete Freund’s adjuvant (CFA) only (Fig. 1c—an additional movie depicts representative HL responses)
When the HL-evoked flavoprotein autofluorescence imaging (FAI) signal was analyzed in the temporal domain, we found that the overall signal duration—the time between stimulus onset and signal offset—was prolonged in the EAE group when compared to CFA-only or naïve animals
Summary
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. Wide-spread gray matter synaptopathy, driven by diffuse and persistent neuroinflammation throughout the central nervous system (CNS) is emerging as a critical contributing factor in the loss of function, sensory and cognitive abnormalities [11], and potentially in pain—which is known to feature prominently EAE. These reports provide an experimental foundation for investigations into the connections between these phenomena in diseases like MS/EAE. While a few previous reports have highlighted the existence of altered neuronal structure and function in the neocortex of animals with EAE [19,20,21], no study to date has directly examined changes in neuronal activity and structure in higher sensory cortex in connection with altered pain behaviors in the early stages of the disease
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
