OSCR

Brainstem enkephalinergic neural circuit underlying cold-induced pain relief in mice.

Overview

Authors: Hayun Kim1, Yoonkyung Lee1, Seog Bae Oh1,2,3
ORCID iDs: Hayun Kim, Yoonkyung Lee, Seog Bae Oh
  1. Interdisciplinary Program in Neuroscience, Seoul National University, Seoul 08826, Republic of Korea
  2. Department of Neurobiology and Physiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea
  3. ADA Forsyth Institute, Cambridge, MA, USA
Institutions: Seoul National University (South Korea)
Journal: Science advances, volume 12, issue 45, article eaea3106
Dates: received 6 July 2025; accepted 30 September 2026; published online 6 November 2026; in print November 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1126/sciadv.aea3106 · PMID 42993824 · PMCID PMC13742151 · OpenAlex W4416231450
Open access: gold, a free copy (OpenAlex)
Preprint: doi:10.1101/2025.11.10.686886
Status: data only (how the code is found and verified)
Categories: mouse (organism), pain (population), cellular / molecular (subfield)
Methods: Statistics, Machine learning, Single-unit activity, calcium imaging
MeSH: Brain Stem*, Cold Temperature*, Enkephalins*, Pain*, Pain Management*, Analgesia, Animals, Male, Mice, Neurons, Parabrachial Nucleus, Periaqueductal Gray, Protein Precursors, TRPM Cation Channels (* major topic)
Topic: Pain Mechanisms and Treatments (Physiology (medical), Medicine), according to OpenAlex
Funding: National Research Foundation of Korea (RS-2023-00264409, RS‐ 2021‐NR059709, RS‐2024‐00441103); Ministry of Science and ICT, South Korea
Citations: not cited yet (Europe PMC); 83 references in the paper

Abstract

Application of cold or cold-mimicking chemicals to injury has long been recognized as an effective means of pain relief. However, underlying neural mechanisms remain elusive. Here, we identified a cold-responsive neuronal subset within the lateral parabrachial nucleus (lPBN), the thermosensory relay region in the hindbrain, that mediates cold-induced analgesia in mice. Activation of these neurons and their projection to ventrolateral periaqueductal gray (vlPAG) increased the nociceptive threshold, while ablation of these neurons attenuated analgesia induced by cold-mimicking chemicals. We further identified that these neurons express precursor gene of enkephalin (Penk), which is necessary for TRPM8 (transient receptor potential melastatin 8)–mediated pain relief. Mechanistically, cold-responsive lPBN neurons frequency-dependently released enkephalin peptide into vlPAG to activate the descending pain modulation circuitry via disinhibition. Activation of cold-responsive neurons reduced spinal cord responses to noxious stimuli, suggesting the involvement of a top-down pain modulation pathway. These findings propose a central mechanism underlying cold-induced pain relief, which could be a novel therapeutic target.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data and to no code of its authors: see the Data section.

The paper's code and data availability statement is in the Data section.

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Data

Data links

Data, code, and materials availability

This study did not generate new, unique reagents. All data needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials. Raw sequencing data are deposited to BioSample Sequence Read Archive (SRA) under the accession number SAMN56581791-SAMN56581799 (www.ncbi.nlm.nih.gov/sra/?term=SAMN56581791 to www.ncbi.nlm.nih.gov/sra/?term=SAMN56581799) and are publicly available. This paper does not report any original code.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 9 November 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 3 authors, 14 MeSH terms, 2 funders, 82 references.

Cite

This paper

Kim, H., Lee, Y., & Oh, S. B. (2026). Brainstem enkephalinergic neural circuit underlying cold-induced pain relief in mice. Science advances, 12(45), eaea3106. https://doi.org/10.1126/sciadv.aea3106

BibTeX

@article{kim2026brainstem,
author = {Kim, Hayun and Lee, Yoonkyung and Oh, Seog Bae},
title = {{Brainstem enkephalinergic neural circuit underlying cold-induced pain relief in mice}},
journal = {Science advances},
year = {2026},
month = nov,
volume = {12},
number = {45},
pages = {eaea3106},
publisher = {American Association for the Advancement of Science},
issn = {2375-2548},
doi = {10.1126/sciadv.aea3106},
url = {https://doi.org/10.1126/sciadv.aea3106},
pmid = {42993824},
pmcid = {PMC13742151}
}

RIS

TY - JOUR
AU - Kim, Hayun
AU - Lee, Yoonkyung
AU - Oh, Seog Bae
TI - Brainstem enkephalinergic neural circuit underlying cold-induced pain relief in mice
T2 - Science advances
J2 - Sci Adv
PY - 2026
DA - 2026/11/06
VL - 12
IS - 45
SP - eaea3106
SN - 2375-2548
PB - American Association for the Advancement of Science
DO - 10.1126/sciadv.aea3106
UR - https://doi.org/10.1126/sciadv.aea3106
LA - en
ER -

CSL-JSON

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