Multiple sclerosis (MS) is an autoimmune-inflammatory
neurodegenerative disease that is often accompanied by a debilitating
neuropathic pain. Disease-modifying agents slow down the progression of
multiple sclerosis and prevent relapses, yet it remains unclear if they yield
analgesia. We explored the
analgesic potential of
fingolimod (
FTY720), an agonist and/or functional antagonist at the
sphingosine-1-phosphate receptor 1 (S1PR1), because it reduces
hyperalgesia in models of peripheral inflammatory and
neuropathic pain. We used a
myelin oligodendrocyte glycoprotein 35 to 55 (MOG35-55) mouse model of
experimental autoimmune encephalomyelitis, modified to avoid frank
paralysis, and thus, allow for assessment of withdrawal behaviors to somatosensory stimuli. Daily intraperitoneal
fingolimod reduced behavioral signs of central
neuropathic pain (mechanical and
cold hypersensitivity) in a dose-dependent and reversible manner. Both autoimmune
encephalomyelitis and
fingolimod changed
hyperalgesia before modifying motor function, suggesting that
pain-related effects and clinical neurological deficits were modulated independently.
Fingolimod also reduced cellular markers of central sensitization of neurons in the dorsal horn of the spinal cord:
glutamate-evoked Ca signaling and stimulus-evoked phospho-extracellular signal-related
kinase ERK (pERK) expression, as well as upregulation of astrocytes (GFAP) and macrophage/microglia (Iba1) immunoreactivity. The antihyperalgesic effects of
fingolimod were prevented or reversed by the S1PR1 antagonist W146 (1 mg/kg daily, i.p.) and could be mimicked by either repeated or single injection of the S1PR1-selective agonist
SEW2871.
Fingolimod did not change spinal membrane S1PR1 content, arguing against a functional antagonist mechanism. We conclude that
fingolimod behaves as an S1PR1 agonist to reduce
pain in
multiple sclerosis by reversing central sensitization of spinal nociceptive neurons.