Ozanimod and other sphingosine-1-phosphate receptor 1 modulators normalize neuropathic injury-enhanced inhibition of central lateral amygdala neurons expressing corticotropin-releasing hormone.

A key brain structure in the processing of chronic pain is the central nucleus of the amygdala (CeA), which has justifiably been termed the "nociceptive amygdala." Prior work shows that a major subclass of neurons in the lateral region of the CeA (CeL) expressing corticotropin-releasing hormone (CRH; CeLCRH + neurons) is sensitized in the acute, but not chronic, stage of neuropathic pain. However, the signal transduction regulation of synaptic activity in CeLCRH + neurons remains poorly understood. The goal of this work was to elucidate the modulation of CeLCRH + neuron synaptic activity by sphingosine-1-phosphate receptor 1 (S1PR1) signaling in neuropathic pain. Here we performed whole-cell patch-clamp electrophysiological recordings in acute brain slices from male mice subjected to the spared nerve injury (SNI) model of neuropathic pain to measure how pharmacological modulation of S1PR1 alters synaptic properties of CeLCRH + neurons. In sham, but not SNI mouse, we found S1PR1 agonism reduced the frequency of excitatory input onto CeLCRH + neurons, while S1PR1 antagonism had no effect on either surgical group. We also show SNI increased the frequency of inhibitory input onto CeLCRH + neurons which was normalized by both an S1PR1 agonist and antagonist, as well as the clinically relevant S1PR1,5 agonist, Ozanimod. Together, our data suggest SNI alters excitatory and inhibitory inputs onto CeLCRH + neurons, and each type of input is differentially modulated by S1PR1 signaling, highlighting CeLCRH + neurons as key nodes in neuropathic pain circuitry and identifying S1PR1s as a potential target for the development of new analgesic pharmacotherapies.