title: Advances in the management of multiple sclerosis spasticity: multiple sclerosis spasticity nervous pathways.
abstract: BACKGROUND
  Spasticity arises from hyperexcitability of the neural stretch reflex arc secondary to injury of the corticospinal tract. In response to injury, the density of glutamatergic inputs from afferent 1A fibers to motor neurons increases dramatically and adaptive changes occur in the morphology of microglia cells in the spinal cord.
  
  
  CONCLUSIONS
  Involvement of the endocannabinoid system in pathophysiological mechanisms responsible for spasticity has been demonstrated in animal models of MS. Stimulation of cannabinoid (CB)1 receptors reduces the hyperglutamatergic drive from sensory afferents to spinal cord motor neurons and blocks the synaptic effects of activated microglia and pro-inflammatory mediators (e.g. TNF-α) on glutamatergic transmission. Enhancing corticospinal tract excitability through intermittent theta burst stimulation inhibits the stretch reflex and spasticity by promoting long-term potentiation, a form of synaptic plasticity that requires stimulation of CB1 receptors. Evidence indicates that the antispasticity effects of THC:CBD oromucosal spray (Sativex®) are associated with enhanced cortical long-term potentiation. Key Messages: Glutamatergic and GABAergic pathways are involved in the regulation of muscle tone. CB1 receptors, which are associated with movement, postural control, and pain and sensory perception, influence glutamatergic pathways. THC:CBD oromucosal spray was shown to reverse motor cortex plasticity from long-term depression through long-term potentiation of synaptic transmission, thereby restoring, at least in part, effective corticospinal inputs to spinal circuits.
authors.affiliation: UOSD Multiple Sclerosis Clinical and Research Center, Tor Vergata University & Laboratory of Neuroimmunology and Synaptic Plasticity, CERC-Santa Lucia Foundation, Rome, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000818:Animals; D002185:Cannabidiol; D013759:Dronabinol; D004338:Drug Combinations; D063388:Endocannabinoids / Q000378:metabolism; D006801:Humans; D009044:Motor Cortex / Q000187:drug effects / Q000503:physiopathology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000503:physiopathology*; D009125:Muscle Relaxants, Central / Q000627:therapeutic use; D009128:Muscle Spasticity / Q000188:drug therapy* / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D010936:Plant Extracts / Q000627:therapeutic use; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology
chemical_list: D004338:Drug Combinations; D063388:Endocannabinoids; D009125:Muscle Relaxants, Central; D010936:Plant Extracts; D002185:Cannabidiol; D013759:Dronabinol; C587251:nabiximols