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

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.