UC San Diego

Our perception of pain is an important survival mechanism to avoid potentially damaging noxious stimuli. However, chronic pain is debilitating. While opioids remain the best treatment for pain, chronic use can lead to dangerous side effects including addiction, tolerance, and respiratory depression that have contributed to the U.S. Opioid Crisis. A better understanding of the underlying circuitry that modulates pain perception and contributes to opioid analgesia will lead to alternative strategies to suppress pain in the absence of dangerous side effects. The supraspinal descending pain modulatory system (DPMS) shapes pain perception through terminals in spinal cord and is thought to be crucial for opioid analgesia. DPMS release of noradrenaline in the spinal dorsal horn inhibits pain. However, the circuit mechanisms by which the DPMS evokes this release remain unclear. Using anatomy, behavior, slice electrophysiology, and calcium activity measurements in transgenic mice, we establish a major role for the locus coeruleus (LC) in opioid-mediated antinociception. We also define the synaptic inputs by which canonical DPMS nodes, the ventrolateral periaqueductal gray (vlPAG) and rostroventral medulla (RVM), interface with LC. To this end, we discover that a significant portion of opioid antinociception is driven by excitatory output from vlPAG to LC and uncover a previously unstudied opioid-sensitive inhibitory output from RVM to LC, inhibition of which is antinociceptive. We also find that these circuit elements are responsive to noxious stimulation. Finally, we begin to define plasticity within the LC and excitatory inputs to LC in the context of persistent pain. These findings serve to revise circuit models of descending monoaminergic pain modulation and establish promising new targets for pain relief.