A nigro–subthalamo–parabrachial pathway modulates pain-like behaviors

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Abstract

The basal ganglia including the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr) are involved in pain-related responses, but how they regulate pain processing remains unknown. Here, we identify a pathway, consisting of GABAergic neurons in the SNr (SNr ^GABA) and glutamatergic neurons in the STN (STN ^Glu) and the lateral parabrachial nucleus (LPB ^Glu), that modulates acute and persistent pain states in both male and female mice. The activity of STN neurons was enhanced in acute and persistent pain states. This enhancement was accompanied by hypoactivity in SNr ^GABA neurons and strengthening of the STN–LPB glutamatergic projection. Reversing the dysfunction in the SNr ^GABA-STN ^Glu-LPB ^Glu pathway attenuated activity of LPB ^Glu neurons and mitigated pain-like behaviors. Therefore, the SNr ^GABA-STN ^Glu-LPB ^Glu pathway regulates pathological pain and is a potential target for pain management.

Abstract

Maladaptive plastic changes in the brain are critical for pain maintenance. The authors identify a nigro–subthalamo–parabrachial pathway and reveal that reversing a series of neuronal and synaptic malfunctions in this pathway in acute and chronic pain mitigates hyperalgesia, providing potential therapeutic targets for pain modulation.

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Most cited references 65

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Kevin W Eliceiri, Caroline A Schneider, Wayne S Rasband (2018)

For the past twenty five years the NIH family of imaging software, NIH Image and ImageJ have been pioneers as open tools for scientific image analysis. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.

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Central sensitization: implications for the diagnosis and treatment of pain.

Clifford Woolf, John Jarrell (2011)

Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity. Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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Spared nerve injury: an animal model of persistent peripheral neuropathic pain.

Isabelle Decosterd, Clifford Woolf (2000)

Peripheral neuropathic pain is produced by multiple etiological factors that initiate a number of diverse mechanisms operating at different sites and at different times and expressed both within, and across different disease states. Unraveling the mechanisms involved requires laboratory animal models that replicate as far as possible, the different pathophysiological changes present in patients. It is unlikely that a single animal model will include the full range of neuropathic pain mechanisms. A feature of several animal models of peripheral neuropathic pain is partial denervation. In the most frequently used models a mixture of intact and injured fibers is created by loose ligation of either the whole (Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87-107) or a tight ligation of a part (Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 1990;43:205-218) of a large peripheral nerve, or a tight ligation of an entire spinal segmental nerve (Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992;50:355-363). We have developed a variant of partial denervation, the spared nerve injury model. This involves a lesion of two of the three terminal branches of the sciatic nerve (tibial and common peroneal nerves) leaving the remaining sural nerve intact. The spared nerve injury model differs from the Chung spinal segmental nerve, the Bennett chronic constriction injury and the Seltzer partial sciatic nerve injury models in that the co-mingling of distal intact axons with degenerating axons is restricted, and it permits behavioral testing of the non-injured skin territories adjacent to the denervated areas. The spared nerve injury model results in early ( 6 months), robust (all animals are responders) behavioral modifications. The mechanical (von Frey and pinprick) sensitivity and thermal (hot and cold) responsiveness is increased in the ipsilateral sural and to a lesser extent saphenous territories, without any change in heat thermal thresholds. Crush injury of the tibial and common peroneal nerves produce similar early changes, which return, however to baseline at 7-9 weeks. The spared nerve injury model may provide, therefore, an additional resource for unraveling the mechanisms responsible for the production of neuropathic pain.

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Author and article information

Contributors

Jun-Li Cao:

ORCID: http://orcid.org/0000-0002-8932-4743

caojl0310@aliyun.com

Cheng Xiao:

ORCID: http://orcid.org/0000-0001-9649-7450

xchengxj@xzhmu.edu.cn

Chunyi Zhou:

ORCID: http://orcid.org/0000-0003-2290-9234

chunyi.zhou@xzhmu.edu.cn

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 15 December 2022

Publication date PMC-release: 15 December 2022

Publication date Collection: 2022

Volume: 13

Electronic Location Identifier: 7756

Affiliations

[1 ]GRID grid.417303.2, ISNI 0000 0000 9927 0537, Jiangsu Province Key Laboratory in Anesthesiology, School of Anesthesiology, , Xuzhou Medical University, ; 221004 Xuzhou, Jiangsu China

[2 ]GRID grid.417303.2, ISNI 0000 0000 9927 0537, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, , Xuzhou Medical University, ; 221004 Xuzhou, Jiangsu China

[3 ]GRID grid.417303.2, ISNI 0000 0000 9927 0537, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, , Xuzhou Medical University, ; 221004 Xuzhou, Jiangsu China

Author information

Jun-Li Cao http://orcid.org/0000-0002-8932-4743

Cheng Xiao http://orcid.org/0000-0001-9649-7450

Chunyi Zhou http://orcid.org/0000-0003-2290-9234

Article

Publisher ID: 35474

DOI: 10.1038/s41467-022-35474-0

PMC ID: 9755217

PubMed ID: 36522327

SO-VID: 85bb5214-3d3e-425d-a62d-99dc3ae62629

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 7 November 2021

Date accepted : 5 December 2022

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 81971038

Award ID: 82171235

Award Recipient : Chunyi Zhou

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ScienceOpen disciplines: Uncategorized

Keywords: neural circuits,neuropathic pain,neuronal physiology

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ScienceOpen disciplines: Uncategorized

Keywords: neural circuits, neuropathic pain, neuronal physiology

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A nigro–subthalamo–parabrachial pathway modulates pain-like behaviors

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Most cited references 65

NIH Image to ImageJ: 25 years of image analysis

Central sensitization: implications for the diagnosis and treatment of pain.

Spared nerve injury: an animal model of persistent peripheral neuropathic pain.

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Cited by 8

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