Temporal dynamics of locus coeruleus modulation of stress-induced antinociception

Pain and stress are largely interdependent. Targeting stress pathways for pain relief is a novel potential therapeutic strategy. However, to take this approach we need to better understand the mechanisms by which stress influences pain. The locus coeruleus (LC) provides the largest noradrenergic (NE) innervation to the central nervous system and is a major intersection of pain and stress neural circuitry. We seek to determine how stress engages the LC-NE system to alter nociception. Using a cell type-selective inhibitory chemogenetic targeting strategy, we show that inhibition of the LC-NE system reverses acute restraint stress-induced antinociception on a hot plate. However, this chemogenetic strategy lacks the temporal specificity necessary to distinguish whether the LC is required for discrete aspects of stress-induced antinociception, namely the experience of the primary stressor versus noxious stimulus detection and processing. To gain temporal precision for these purposes, we use inhibitory optogenetics to restrict cellular inhibition during either the primary stressor or noxious stimulus only. Our results show that LC activity during the experience of the noxious stimulus is not required to elicit stress-induced antinociception. However, somewhat surprisingly, LC activity is required to maintain normal nociceptive processing in the absence of stress. Given this information, we then sought to characterize endogenous LC activity during our stress-induced antinociception behavioral paradigm using in vivo fiber photometry of global LC calcium activity. In acute restraint stress, we demonstrate that LC calcium activity increases during bouts of struggle against the restraint. Additionally, LC calcium activity is increased during discrete nocifensive responses throughout noxious stimulus detection and processing. Together, our combined chemogenetic, optogenetic, and photometry results suggest the LC tone exerts some level of basal antinociception and that the LC may initiate the process of stress-induced antinociception during the primary stressor rather than during the experience of noxious sensation. Grant support from R01 NS117899-01 F31 NS124301-01.