Calcitonin Gene‐Related Peptide (CGRP)‐Expressing Neurons in the External Lateral Parabrachial Area Regulate Pain‐Induced Sleep Disturbances

Abstract Given that sleep and pain are bidirectionally related, we investigated the neural circuits underlying pain‐induced sleep disturbances using two acute pain models. Activation of nociceptors in acute inflammatory pain (AIP) significantly reduced sleep by 45–50% in the first 6 h, with reduced sleep spindle density for 1–3 h post‐AIP. Additionally, an “optogenetic pain (Opto‐Pain)” model is implemented to produce acute peripheral pain‐induced awakenings that reduced sleep comparable to AIP. Both pain models are used to test the role of wake‐promoting neurons in the parabrachial nucleus that express Calcitonin Gene‐Related Peptide (PBel CGRP ) in relaying nociceptive stimulus from the dorsal horn as part of the spine‐ponto‐amygdaloid tract. Blocking PBel CGRP neurons with genetic ablation or optogenetic inhibition attenuated sleep loss. To dissect the PBel CGRP pathways, the terminals are then optogenetically silenced post‐AIP and found the reversal of sleep disturbances in the following descending order of effectiveness: substantia innominata of the basal forebrain (SI‐BF) > central nucleus of the amygdala (CeA) > bed nucleus of the stria terminalis (BNST) > the lateral hypothalamus (LH). In SI‐BF and CeA, a similar reversal of AIP‐induced sleep loss occurred with pharmacological blocking of either CGRP or NMDA receptors. The results are relevant to emerging pain therapies aiming to attenuate sleep disturbances.