| Autor: |
Lubejko ST; Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.; Neurosciences Graduate Program, University of California San Diego, La Jolla, CA 92093, USA., Livrizzi G; Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.; Biological Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093, USA., Patel J; Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA., Yung JC; Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA., Yaksh TL; Departments of Anesthesiology and Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA., Banghart MR; Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. |
| Abstrakt: |
The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, we establish that noradrenergic neurons of the locus coeruleus (LC) are essential for supraspinal opioid antinociception. Unexpectedly, given prior emphasis on descending serotonergic pathways, we find that opioid antinociception is primarily driven by excitatory output from the ventrolateral periaqueductal gray (vlPAG) to the LC. Furthermore, we identify a previously unknown opioid-sensitive inhibitory input from the rostroventromedial medulla (RVM), the suppression of which disinhibits LC neurons to drive spinal noradrenergic antinociception. We also report the presence of prominent bifurcating outputs from the vlPAG to the LC and the RVM. Our findings significantly revise current models of the DPMS and establish a novel supraspinal antinociceptive pathway that may contribute to multiple forms of descending pain modulation. |
