Glial cell activation and altered metabolic profile in the spinal-trigeminal axis in a rat model of multiple sclerosis associated with the development of trigeminal sensitization

Trigeminal neuralgia is often an early symptom of multiple sclerosis (MS), and it generally does not correlate with the severity of the disease. Thus, whether it is triggered simply by demyelination in specific central nervous system areas is currently questioned. Our aims were to monitor the development of spontaneous trigeminal pain in an animal model of MS, and to analyze: i) glial cells, namely astrocytes and microglia in the central nervous system and satellite glial cells in the trigeminal ganglion, and ii) metabolic changes in the trigeminal system. The subcutaneous injection of recombinant MOG(1-125) protein fragment to Dark Agouti male rats led to the development of relapsing-remitting EAE, with a first peak after 13 days, a remission stage from day 16 and a second peak from day 21. Interestingly, orofacial allodynia developed from day 1 post injection, i.e. well before the onset of EAE, and worsened over time, irrespective of the disease phase. Activation of glial cells both in the trigeminal ganglia and in the brainstem, with no signs of demyelination in the latter tissue, was observed along with metabolic alterations in the trigeminal ganglion. Our data show, for the first time, the spontaneous development of trigeminal sensitization before the onset of relapsing-remitting EAE in rats. Additionally, pain is maintained elevated during all stages of the disease, suggesting the existence of parallel mechanisms controlling motor symptoms and orofacial pain, likely involving glial cell activation and metabolic alterations which can contribute to trigger the sensitization of sensory neurons.