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.
Sci Adv. 2024 Apr 26;10(17):eadj9581. doi: 10.1126/sciadv.adj9581.
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. While much previous work has emphasized the role of 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 describe pain-related activity throughout this circuit and report the presence of prominent bifurcating outputs from the vlPAG to the LC and the RVM. Our findings substantially revise current models of the DPMS and establish a supraspinal antinociceptive pathway that may contribute to multiple forms of descending pain modulation.
脊髓上的下行疼痛调制系统（DPMS）通过单胺能调制脊髓中的感觉信息来塑造疼痛感知。然而，下行去甲肾上腺素能信号的作用和突触机制仍不清楚。在这里，我们确定蓝斑核（LC）的去甲肾上腺素能神经元对于脊髓上阿片类药物的镇痛作用是必不可少的。虽然之前的许多研究都强调了下行 5-羟色胺能通路的作用，但我们发现阿片类药物的镇痛作用主要是由腹外侧导水管周围灰质（vlPAG）到 LC 的兴奋性输出驱动的。此外，我们发现了一个以前未知的来自头端腹内侧髓质（RVM）的阿片类药物敏感的抑制性输入，抑制它会解除 LC 神经元的抑制，从而驱动脊髓去甲肾上腺素能镇痛。我们描述了整个回路中的疼痛相关活动，并报告了来自 vlPAG 到 LC 和 RVM 的突出分叉输出的存在。我们的发现极大地修正了 DPMS 的现行模型，并建立了一个可能有助于多种形式的下行疼痛调制的脊髓上镇痛途径。
