Impaired Feedforward Inhibition Of Corticopontine Neurons Drives Placebo Analgesia

• Published in: The journal of pain Vol. 24; no. 4; pp. 23 - 24
• Main Authors: Chen, Chong, Niehaus, Jesse K., Dinc, Fatih, Huang, Karen L., Barnette, Alexander L., Shuster, S. Andrew, Wang, Lihua, Lemire, Andrew L., Menon, Vilas, Ritola, Kimberly, Hantman, Adam, Zeng, Hongkui, Schnitzer, Mark J., Scherrer, Grégory
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.04.2023
• ISSN: 1526-5900; 1528-8447
• DOI: 10.1016/j.jpain.2023.02.081

Pain is a multidimensional experience with sensory-discriminative, affective-motivational and cognitive-evaluative components. Although numerous neurobiological mechanisms underlying the sensory and affective dimensions of pain have been resolved, our understanding of the cognitive modulation of pain remains limited. Here, we identify circuit, cellular and synaptic mechanisms that mediate placebo analgesia, the biomedical phenomenon in which a positive expectation suffices to reduce pain. We developed a 7-day placebo analgesia conditioning (PAC) assay that generates a pain relief expectation in mice and permits evaluation of placebo analgesia. Activity-dependent genetic tagging during PAC revealed that rostral anterior cingulate cortex neurons projecting to the pontine nuclei (rACC→Pn neurons) contribute to placebo analgesia. Calcium imaging in freely moving mice trained to expect pain relief revealed a correlated increase in the activity and synchrony of rACC→Pn neurons during pain relief expectations. Whole-cell patch-clamp recording indicated that PAC increases the burst firing, AMPA/NMDA ratio and synaptic plasticity of rACC→Pn neurons, while impairing the efficiency and timing of their feedforward inhibition. Photoinhibition of the rACC-Pn pathway reversed PAC-induced analgesia. Single-cell transcriptomics suggested that 54% of Pn neurons express Oprd1 (encoding the delta opioid receptor). Additionally, photoinhibition of Oprd1+ Pn neurons abolished PAC-induced analgesia. These findings advance our current understanding of placebo analgesia and cognitive modulation of pain, from the merely brain-area level to the circuit, cellular and synaptic levels, bridge the gap with our more advanced understanding of the sensory and affective dimensions of pain, and open the possibility of using this pathway to promote positive outcomes during pain management. National Institutes of Health grant R01NS106301 (G.S.), New York Stem Cell Foundation (G.S.), Stanford School of Medicine Dean's Fellowship (C.C.).