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; CeL CRH+ neurons) is sensitized in the acute, but not chronic, stage of neuropathic pain. However, the signal transduction regulation of synaptic activity in CeL CRH+ neurons remains poorly understood. The goal of this work was to elucidate the modulation of CeL CRH+ neuron synaptic activity by sphingosine-1-phosphate receptor 1 (S1PR 1 ) 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 S1PR 1 alters synaptic properties of CeL CRH+ neurons. In sham, but not SNI mouse, we found S1PR 1 agonism reduced the frequency of excitatory input onto CeL CRH+ neurons, while S1PR 1 antagonism had no effect on either surgical group. We also show SNI increased the frequency of inhibitory input onto CeL CRH+ neurons which was normalized by both an S1PR 1 agonist and antagonist, as well as the clinically relevant S1PR 1,5 agonist, Ozanimod. Together, our data suggest SNI alters excitatory and inhibitory inputs onto CeL CRH+ neurons, and each type of input is differentially modulated by S1PR 1 signaling, highlighting CeL CRH+ neurons as key nodes in neuropathic pain circuitry and identifying S1PR 1 s as a potential target for the development of new analgesic pharmacotherapies. • Nerve injury enhances inhibitory input to central amygdala stress-peptide neurons. • Sphingosine-1-phosphate receptor-1 agonist reduces excitation in uninjured state. • Sphingosine-1-phosphate receptor-1 agonist reduces injury-evoked inhibition. • Ozanimod normalizes nerve-injury-induced increase in inhibitory synaptic input
Hines et al. (Wed,) studied this question.