Pathophysiology of Neuropathic Pain in Multiple Sclerosis: a Review

Neuropathic pain is one of the most relevant symptoms in multiple sclerosis (MS) and is a key contributor to the impaired quality of life in this disease. A better understanding of MS-related neuropathic pain is needed to develop new drugs and improve the use of available ones. In this review, we cover existing knowledge on the pathophysiology of neuropathic pain in patients with MS. Our current understanding of this disorder stems from studies conducted on MS, other diseases responsible for neuropathic pain, and animal models of demyelinating disorders, like experimental autoimmune encephalomyelitis. Responsible mechanisms are complex and can act at different levels. At the molecular and cellular scale, neuronal hyperexcitability is the main driver of neuropathic pain; it is the final consequence of other interacting events taking place on the cell membrane and in the intracellular and extracellular environment. Impairment of inhibitory neurotransmission further enhances hyperexcitability. Functional alterations of complex neuronal networks can be observed at higher levels, showing that modifications of the dynamic pain connectome play a relevant role in the pathogenesis of pain. Moreover, in recent years a distinction has been drawn between neuropathic and nociplastic pain; the consequences of this new classification on pathophysiological models of MS-related neuropathic pain are not still fully understood and deserve future attention.