Neurons in the caudal ventral lateral medulla mediate descending pain control

Supraspinal brain regions modify nociceptive signals in response to various stressors including stimuli which elevate pain thresholds. The medulla oblongata has previously been implicated in this type of pain control, but the neurons and molecular circuits involved have remained elusive. Here we identify catecholaminergic neurons in the caudal ventrolateral medulla that are activated by noxious stimuli in mice. Upon activation, these neurons produce bilateral feed-forward inhibition that attenuates nociceptive responses through a pathway involving the locus coeruleus and noradrenalin in the spinal cord. This pathway is sufficient to attenuate injury-induced heat allodynia and is required for counter-stimulus induced analgesia to noxious heat. Our findings define a component of the pain modulatory system that regulates nociceptive responses., Animals
All experiments using mice followed National Institutes of Health (NIH) guidelines and were approved by the National Institute of Dental and Craniofacial Research (NIDCR) ACUC. Mice were housed in small social groups (4–5 animals) in individually ventilated cages under 12-h light/dark cycles and fed ad libitum. Animals of both sexes aged 7–12 weeks were used in experiments. C57BL/6N wild-type mice were purchased from Envigo. TH-IRES-CreER mice (The Jackson Laboratory, 00852), TH-IRES-Cre mice (European Mouse Mutant Archive; stock no. EM:00254; backcrossed five generations with C57BL/6NJ mice) and Ai9 reporter mice (The Jackson Laboratory, 007909) were bred in-house. Animals were randomly allocated to the different experimental conditions reported in this study. Genotyping of offspring from all breeding steps was performed with genomic DNA isolated from tail snips.
Viral vectors
AAV2/5-Ef1a-DIO hChR2(E123T/T159C)-EYFP, AAV1-hSyn-Cre, AAV9-CAG-FLEX-GCaMP6s-WPRE-SV40 and AAV9-hSyn-..., , # Neurons in the caudal ventral lateral medulla mediate descending pain control

[https://doi.org/10.5061/dryad.kkwh70s82](https://doi.org/10.5061/dryad.kkwh70s82)

We identify catecholaminergic neurons in the caudal ventrolateral medulla that are activated by noxious stimuli in mice. With fiber photometry, optogenetics and animal behavior, we demonstrated that these neurons produce bilateral feed-forward inhibition that attenuates nociceptive responses through a pathway involving the locus coeruleus and norepinephrine in the spinal cord upon activation.

## Description of the data and file structure

1. Data are the source data for figures and images published in the following paper.
Gu, X., Zhang, Y.Z., O’Malley, J.J. *et al.* Neurons in the caudal ventrolateral medulla mediate descending pain control. *Nat Neurosci* **26**, 594–605 (2023). https://doi.org/10.1038/s41593-023-01268-w
2. Source data for bar graphs were organized in the excel files. Data in “\*.xlsx” for each figure ...