Endogenous opioids gate the locus coeruleus pain generator

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The locus coeruleus (LC) plays a paradoxical role in chronic pain. Although largely known as a potent source of endogenous analgesia, increasing evidence suggests injury can transform the LC into a chronic pain generator. We sought to clarify the role of this system in pain. Here, we show optogenetic inhibition of LC activity is acutely antinociceptive. Following long-term spared nerve injury, the same LC inhibition is analgesic – further supporting its pain generator function. To identify inhibitory substrates that may naturally serve this function, we turned to endogenous LC mu opioid receptors (LC-MOR). These receptors provide powerful LC inhibition and exogenous activation of LC-MOR is antinociceptive. We therefore hypothesized that endogenous LC-MOR-mediated inhibition is critical to how the LC modulates pain. Using cell type-selective conditional knockout and rescue of LC-MOR receptor signaling, we show these receptors bidirectionally regulate thermal and mechanical hyperalgesia – providing a functional gate on the LC pain generator.

Article activity feed

  1. To ensure a smooth transition from therestraint stress to hot plate testing, we outfitted mice with a head-fixation bracket around bilateralfiber optic implants above the LC

    it would be great to see a picture of the bracket!

  2. Figure

    Minor legibility note on panels E and F: it is difficult to distinguish the injured vs non-injured mCherry and stGtACR2 line markers, especially since there is also blue shading on the "stim"

  3. Altogether, these resultssuggest rescued mu opioid receptor function may be a therapeutic target for the treatment chronicpain

    could be promising but challenging from regulatory point of view given the opioid crisis.