Identifying the pathways required for coping behaviours associated with sustained pain
Open accessAbstract
Animals and humans display two types of response to noxious stimuli. The first includes reflexive defensive responses that prevent or limit injury; a well-known example of these responses is the quick withdrawal of one's hand upon touching a hot object. When the first-line response fails to prevent tissue damage (for example, a finger is burnt), the resulting pain invokes a second-line coping response-such as licking the injured area to soothe suffering. However, the underlying neural circuits that drive these two strings of behaviour remain poorly understood. Here we show in mice that spinal neurons marked by coexpression of TAC1 Cre and LBX1 Flpo drive coping responses associated with pain. Ablation of these spinal neurons led to the loss of both persistent licking and conditioned aversion evoked by stimuli (including skin pinching and burn injury) that-in humans-produce sustained pain, without affecting any of the reflexive defensive reactions that we tested. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei 1-3. Consistently, spinal TAC1-lineage neurons are connected to medial thalamic nuclei by direct projections and via indirect routes through the superior lateral parabrachial nuclei. Furthermore, the anatomical and functional segregation observed at the spinal level also applies to primary sensory neurons. For example, in response to noxious mechanical stimuli, MRGPRD- and TRPV1-positive nociceptors are required to elicit reflexive and coping responses, respectively. Our study therefore reveals a fundamental subdivision within the cutaneous somatosensory system, and challenges the validity of using reflexive defensive responses to measure sustained pain.
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The Sox5 dorsal excitatory family comprised Excit-14, Excit-15, Excit-16, Excit-17, Excit-18, and Excit-19 and expressed markers suggestive of a role in coping pain and mechanical nociception.
“The Sox5 dorsal, the excitatory family was comprised of Excit-14, Excit-15, Excit-16, Excit-17, Excit-18, and Excit-19, and expressed markers suggestive of a role in coping pain and mechanical nociception46,52,56,63–67.”
From A harmonized atlas of mouse spinal cord cell types and their spatial organization (2021) · cites this paper as [63]
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- Authors
- Huang, T., Lin, S.-H., Malewicz, N. M., Zhang, Y., Zhang, Y., Goulding, M., LaMotte, R. H., & Ma, Q.
- Affiliations
- Harvard University (US)
- Yale University (US)
- Wannan Medical College (CN)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Ma, Qiufu
- Venue
- Nature
- Published
- 2018-12-10
- Volume
- 565
- Issue
- 7737
- Pages
- 86-90
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6461409
- OpenAlex
- W2904345154
- Cited by
- 264
- References
- 56
- Citations by year
- 2026: 33 · 2025: 39 · 2024: 39 · 2023: 30 · 2022: 47 · 2021: 29 · 2020: 34 · 2019: 12
- FWCI
- 12.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Wellcome Trust (200183/Z/15/Z)
- National Institute of Neurological Disorders and Stroke (R01NS086372)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR070875)
- National Institute of Dental and Craniofacial Research (R01DE018025)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Keywords
- sustained pain, coping behaviour, licking behavior, conditioned aversion, spinal cord neurons, TAC1, Lbx1, medial thalamic nuclei, nociceptors, MRGPRD, TRPV1
- MeSH terms
- Adaptation, Psychological, Animals, Avoidance Learning, Conditioning, Classical, Female, Humans, Male, Neural Pathways, Neurons, Afferent, Protein Precursors, Tachykinins, Mediodorsal Thalamic Nucleus, Receptors, G-Protein-Coupled, TRPV Cation Channels, Mice, Chronic Pain, Parabrachial Nucleus
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