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1
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Li X, Yang Y, Huang D, Ma J, Huang Y. Pulsed Radiofrequency Relieves Neuropathic Pain by Repairing the Ultrastructural Damage of Chronically Compressed Dorsal Root Ganglion. Neurosci Insights 2025; 20:26331055251339081. [PMID: 40438732 PMCID: PMC12117237 DOI: 10.1177/26331055251339081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 04/16/2025] [Indexed: 06/01/2025] Open
Abstract
Pulsed radiofrequency (PRF) has demonstrated therapeutic potential for neuropathic pain, yet its efficacy in alleviating pain induced by chronic dorsal root ganglion (DRG) compression remains unclear. This study evaluated the analgesic effects of DRG-targeted PRF in a chronic compression of DRG (CCD) rat model. Adult male Sprague Dawley rats were divided into four groups: sham, CCD, CCD+PRF, and CCD+freePRF. CCD was induced by inserting stainless-steel rods into the intervertebral foramen to compress L4/L5 DRGs. Pain behaviors, including spontaneous pain, mechanical/cold allodynia, and heat hypersensitivity, were assessed pre- and post-PRF treatment. On day 14 post-CCD, DRG ultrastructural changes and myelin basic protein (MBP) expression were analyzed via transmission electron microscopy and immunofluorescence. Compared to sham rats, CCD animals exhibited significant pain behaviors (P < .0001). PRF treatment in CCD+PRF rats significantly attenuated these behaviors (P < .01). Ultrastructural analysis revealed intact myelin sheaths in sham DRGs, whereas CCD DRGs showed myelin damage and reduced MBP expression (P < .01). Notably, PRF repaired myelin structural integrity and restored MBP levels. These findings demonstrate that DRG PRF alleviates neuropathic pain by reversing ultrastructural damage caused by chronic compression, providing mechanistic insights into PRF's analgesic effects and supporting its therapeutic value for neuropathic pain management.
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Affiliation(s)
- Xuelian Li
- Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South University, Changsha, China
| | - Ying Yang
- Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South University, Changsha, China
- Hunan Key Laboratory of Nanophotonics and Devices, Hunan Key Laboratory of Super-Microstructure and Ultrafast Process, School of Physics, Central South University, Changsha, China
| | - Dong Huang
- Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South University, Changsha, China
- Hunan Key Laboratory of Brain Homeostasis, Central South University, Changsha, China
| | - Jiahui Ma
- Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South University, Changsha, China
| | - Yuzhao Huang
- Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South University, Changsha, China
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, China
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2
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Diwan AD, Melrose J. Intervertebral disc degeneration and how it leads to low back pain. JOR Spine 2023; 6:e1231. [PMID: 36994466 PMCID: PMC10041390 DOI: 10.1002/jsp2.1231] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 09/23/2022] [Accepted: 10/21/2022] [Indexed: 11/16/2022] Open
Abstract
The purpose of this review was to evaluate data generated by animal models of intervertebral disc (IVD) degeneration published in the last decade and show how this has made invaluable contributions to the identification of molecular events occurring in and contributing to pain generation. IVD degeneration and associated spinal pain is a complex multifactorial process, its complexity poses difficulties in the selection of the most appropriate therapeutic target to focus on of many potential candidates in the formulation of strategies to alleviate pain perception and to effect disc repair and regeneration and the prevention of associated neuropathic and nociceptive pain. Nerve ingrowth and increased numbers of nociceptors and mechanoreceptors in the degenerate IVD are mechanically stimulated in the biomechanically incompetent abnormally loaded degenerate IVD leading to increased generation of low back pain. Maintenance of a healthy IVD is, thus, an important preventative measure that warrants further investigation to preclude the generation of low back pain. Recent studies with growth and differentiation factor 6 in IVD puncture and multi-level IVD degeneration models and a rat xenograft radiculopathy pain model have shown it has considerable potential in the prevention of further deterioration in degenerate IVDs, has regenerative properties that promote recovery of normal IVD architectural functional organization and inhibits the generation of inflammatory mediators that lead to disc degeneration and the generation of low back pain. Human clinical trials are warranted and eagerly anticipated with this compound to assess its efficacy in the treatment of IVD degeneration and the prevention of the generation of low back pain.
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Affiliation(s)
- Ashish D. Diwan
- Spine Service, Department of Orthopaedic Surgery, St. George & Sutherland Clinical SchoolUniversity of New South WalesSydneyNew South WalesAustralia
| | - James Melrose
- Raymond Purves Bone and Joint Research LaboratoryKolling Institute, Sydney University Faculty of Medicine and Health, Northern Sydney Area Health District, Royal North Shore HospitalSydneyNew South WalesAustralia
- Graduate School of Biomedical EngineeringThe University of New South WalesSydneyNew South WalesAustralia
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3
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Uranbileg B, Ito N, Kurano M, Kano K, Uchida K, Sumitani M, Aoki J, Yatomi Y. Inhibition of autotaxin activity ameliorates neuropathic pain derived from lumbar spinal canal stenosis. Sci Rep 2021; 11:3984. [PMID: 33597645 PMCID: PMC7889906 DOI: 10.1038/s41598-021-83569-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 02/04/2021] [Indexed: 12/13/2022] Open
Abstract
Lumbar spinal canal stenosis (LSS) or mechanical compression of dorsal root ganglion (DRG) is one of the causes of low back pain and neuropathic pain (NP). Lysophosphatidic acid (LPA) is a potent bioactive lipid mediator that is produced mainly from lysophosphatidylcholine (LPC) via autotaxin (ATX) and is known to induce NP via LPA1 receptor signaling in mice. Recently, we demonstrated that LPC and LPA were higher in cerebrospinal fluid (CSF) of patients with LSS. Based on the possible potential efficacy of the ATX inhibitor for NP treatment, we used an NP model with compression of DRG (CD model) and investigated LPA dynamics and whether ATX inhibition could ameliorate NP symptoms, using an orally available ATX inhibitor (ONO-8430506) at a dose of 30 mg/kg. In CD model, we observed increased LPC and LPA levels in CSF, and decreased threshold of the pain which were ameliorated by oral administration of the ATX inhibitor with decreased microglia and astrocyte populations at the site of the spinal dorsal horn projecting from injured DRG. These results suggested possible efficacy of ATX inhibitor for the treatment of NP caused by spinal nerve root compression and involvement of the ATX-LPA axis in the mechanism of NP induction.
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Affiliation(s)
- Baasanjav Uranbileg
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobuko Ito
- Department of Anesthesiology and Pain Relief Center, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Makoto Kurano
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Kanji Uchida
- Department of Anesthesiology and Pain Relief Center, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Masahiko Sumitani
- Department of Pain and Palliative Medicine, The University of Tokyo Hospital, Tokyo, Japan
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
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KC E, Moon HC, Kim S, Kim HK, Won SY, Hyun S, Park YS. Optical Modulation on the Nucleus Accumbens Core in the Alleviation of Neuropathic Pain in Chronic Dorsal Root Ganglion Compression Rat Model. Neuromodulation 2019; 23:167-176. [DOI: 10.1111/ner.13059] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 08/20/2019] [Accepted: 09/10/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Elina KC
- Department of NeuroscienceCollege of Medicine, Chungbuk National University Cheongju South Korea
| | - Hyeong Cheol Moon
- Department of NeuroscienceCollege of Medicine, Chungbuk National University Cheongju South Korea
- Department of NeurosurgeryChungbuk National University Hospital Cheongju South Korea
| | - Soochong Kim
- Laboratory of Veterinary Pathology and Platelets Signaling, College of Veterinary Medicine, Chungbuk National University Cheongju South Korea
| | - Hyong Kyu Kim
- Department of Medicine and MicrobiologyChungbuk National University Cheongju South Korea
| | - So Yoon Won
- Department of Biochemistry and Medical Research CenterChungbuk National University Cheongju South Korea
| | - Sang‐Hwan Hyun
- Laboratory of Veterinary Embryology and Biotechnology, College of Veterinary Medicine, Chungbuk National University Cheongju South Korea
- Institute of Stem Cell & Regenerative Medicine, Chungbuk National University Cheongju South Korea
| | - Young Seok Park
- Department of NeuroscienceCollege of Medicine, Chungbuk National University Cheongju South Korea
- Department of NeurosurgeryChungbuk National University Hospital Cheongju South Korea
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5
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Goldschmidt E, Fellows-Mayle W, Paschel EE, Niranjan A, Flickinger JC, Lunsford LD, Gerszten PC. Evaluation of Clinical and Histologic Effects of High-Dose Radiosurgery on Rat Dorsal Root Ganglion. World Neurosurg 2019; 124:e276-e280. [PMID: 30593969 DOI: 10.1016/j.wneu.2018.12.082] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 12/07/2018] [Accepted: 12/10/2018] [Indexed: 11/26/2022]
Abstract
BACKGROUND Stereotactic radiosurgery (SRS) is an effective technique to create lesions of the trigeminal nerve to treat refractory trigeminal neuralgia. In the lumbar spine, the dorsal root ganglion (DRG) contains the body of the sensory neurons responsible for pain sensitivity. Neuromodulation of the DRG might therefore improve chronic peripheral pain. This study was performed to determine the feasibility, clinical, and histologic effects of delivering high-dose SRS targeted to the lumbar DRG in a rat model. METHODS Four Sprague Dawley male rats underwent 80 Gy maximum-dose single-fraction SRS to the left L5 and L6 DRG using the Leksell Gamma Knife Icon (Elekta, Atlanta, Georgia, USA). The right L5 and L6 DRGs served as controls. The animals were evaluated for motor and sensory deficits every 2 weeks and were sacrificed at 3 and 6 months after SRS. Common histologic techniques were used to assess for fibrosis and demyelination at the target levels. RESULTS No detectable motor or sensory deficits were seen in any animal. Histologic changes including fibrosis and loss of myelin were noted to the left L5 and L6 DRGs, but not the right side control DRGs. Fibrotic changes within the vertebral body were also evident on the treated sides of the vertebral bodies. CONCLUSIONS We were able to detect a demyelinating response from SRS delivered to the DRG in rats. Because such changes mimic those seen after trigeminal SRS in experimental animals, we hypothesize that radiosurgery may be a potential option in chronic spinal radicular pain amenable to neuromodulation.
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Affiliation(s)
- Ezequiel Goldschmidt
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Wendy Fellows-Mayle
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Erin E Paschel
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Ajay Niranjan
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - John C Flickinger
- Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - L Dade Lunsford
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Peter C Gerszten
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
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6
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Role of Na V1.6 and Na Vβ4 Sodium Channel Subunits in a Rat Model of Low Back Pain Induced by Compression of the Dorsal Root Ganglia. Neuroscience 2019; 402:51-65. [PMID: 30699332 DOI: 10.1016/j.neuroscience.2019.01.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 01/08/2019] [Accepted: 01/11/2019] [Indexed: 01/18/2023]
Abstract
Low back pain is a common cause of chronic pain and disability. It is modeled in rodents by chronically compressing the lumbar dorsal root ganglia (DRG) with small metal rods, resulting in ipsilateral mechanical and cold hypersensitivity, and hyperexcitability of sensory neurons. Sodium channels are implicated in this hyperexcitability, but the responsible isoforms are unknown. In this study, we used siRNA-mediated knockdown of the pore-forming NaV1.6 and regulatory NaVβ4 sodium channel isoforms that have been previously implicated in a different model of low back pain caused by locally inflaming the L5 DRG. Knockdown of either subunit markedly reduced spontaneous pain and mechanical and cold hypersensitivity induced by DRG compression, and reduced spontaneous activity and hyperexcitability of sensory neurons with action potentials <1.5 msec (predominately cells with myelinated axons, based on conduction velocities measured in a subset of cells) 4 days after DRG compression. These results were similar to those previously obtained in the DRG inflammation model and some neuropathic pain models, in which sensory neurons other than nociceptors seem to play key roles. The cytokine profiles induced by DRG compression and DRG inflammation were also very similar, with upregulation of several type 1 pro-inflammatory cytokines and downregulation of type 2 anti-inflammatory cytokines. Surprisingly, the cytokine profile was largely unaffected by NaVβ4 knockdown in either model. The NaV1.6 channel, and the NaVβ4 subunit that can regulate NaV1.6 to enhance repetitive firing, play key roles in both models of low back pain; targeting the abnormal spontaneous activity they generate may have therapeutic value.
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7
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Shi C, Qiu S, Riester SM, Das V, Zhu B, Wallace AA, van Wijnen AJ, Mwale F, Iatridis JC, Sakai D, Votta-Velis G, Yuan W, Im HJ. Animal models for studying the etiology and treatment of low back pain. J Orthop Res 2018; 36:1305-1312. [PMID: 28921656 PMCID: PMC6287742 DOI: 10.1002/jor.23741] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 09/13/2017] [Indexed: 02/04/2023]
Abstract
Chronic low back pain is a major cause of disability and health care costs. Effective treatments are inadequate for many patients. Animal models are essential to further understanding of the pain mechanism and testing potential therapies. Currently, a number of preclinical models have been developed attempting to mimic aspects of clinical conditions that contribute to low back pain (LBP). This review focused on describing these animal models and the main behavioral tests for assessing pain in each model. Animal models of LBP can be divided into the following five categories: Discogenic LBP, radicular back pain, facet joint osteoarthritis back pain, muscle-induced LBP, and spontaneous occurring LBP models. These models are important not only for enhancing our knowledge of how LBP is generated, but also for the development of novel therapeutic regimens to treat LBP in patients. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1305-1312, 2018.
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Affiliation(s)
- Changgui Shi
- Department of Orthopedic Surgery, Changzheng Hospital,
Second Military Medical University of China, Shanghai, China
| | - Sujun Qiu
- Department of Orthopedic Surgery, Zhujiang Hospital,
Southern Medical University, Guangzhou, China
| | - Scott M. Riester
- Department of Orthopedic Surgery, Mayo Clinic, Rochester,
Minnesota
| | - Vaskar Das
- Department of Biochemistry, Rush University Medical Center,
Chicago, Illinois
| | - Bingqian Zhu
- Departments of Biobehavioral Health Science, University of
Illinois at Chicago (UIC), Chicago, Illinois
| | | | | | - Fackson Mwale
- Department of Surgery, McGill University and Orthopaedic
Research Laboratory, Lady Davis Institute for Medical Research, SMBD-Jewish General
Hospital, Montreal, Canada
| | - James C. Iatridis
- Leni & Peter May Department of Orthopaedics, Icahn
School of Medicine at Mount Sinai, New York, New York
| | - Daisuke Sakai
- Department of Orthopaedic Surgery, Tokai University School
of Medicine, Kanagawa, Japan
| | - Gina Votta-Velis
- Department of Anesthesiology, University of Illinois at
Chicago (UIC), Chicago, Illinois,,Jesse Brown Veterans Affairs Medical Center (JBVAMC) at
Chicago, Chicago, Illinois
| | - Wen Yuan
- Department of Orthopedic Surgery, Changzheng Hospital,
Second Military Medical University of China, Shanghai, China
| | - Hee-Jeong Im
- Jesse Brown Veterans Affairs Medical Center (JBVAMC) at
Chicago, Chicago, Illinois,,Department of Bioengineering, University of Illinois at
Chicago (UIC), Chicago, Illinois
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8
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Perturbing NR2B–PSD-95 interaction relieves neuropathic pain by inactivating CaMKII-CREB signaling. Neuroreport 2017; 28:856-863. [DOI: 10.1097/wnr.0000000000000849] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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9
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Muralidharan A, Park TSW, Mackie JT, Gimenez LGS, Kuo A, Nicholson JR, Corradini L, Smith MT. Establishment and Characterization of a Novel Rat Model of Mechanical Low Back Pain Using Behavioral, Pharmacologic and Histologic Methods. Front Pharmacol 2017; 8:493. [PMID: 28798688 PMCID: PMC5529395 DOI: 10.3389/fphar.2017.00493] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 07/10/2017] [Indexed: 11/22/2022] Open
Abstract
Chronic low back pain (LBP), the leading cause of disability globally, is notoriously difficult to treat. Most rodent models of LBP mimic lumbar radicular pain rather than mechanical LBP. Here, we describe establishment of a new rat model of mechanical LBP that is devoid of a neuropathic component. Groups of adult male Sprague Dawley rats were anesthetized and their lumbar L4/L5 and L5/L6 intervertebral disks (IVDs) were punctured (0.5 mm outer diameter, 2mm-deep) 5 (LPB-5X), or 10 (LBP-10X) times per disk. Sham-rats underwent similar surgery, but without disk puncture. Baseline noxious pressure hyperalgesia of lumbar axial deep tissues, mechanical allodynia in the hindpaws and gait were assessed prior to surgery and once-weekly until study completion on day 49. The model was also characterized using pharmacologic and histologic methods. Good animal health was maintained for ≥ 49 days post-surgery. For LBP- but not sham-rats, there was temporal development of noxious pressure hyperalgesia in lumbar axial deep tissues at days 14–49 post-surgery. Importantly, there were no between-group differences in von Frey paw withdrawal thresholds or gait parameters until study completion. On day 49, significant histologic changes were observed in the L4/L5 and L5/L6 IVDs for LBP-10X rats, but not sham-rats. In LBP-10X rats, single bolus doses of morphine produced dose-dependent relief of primary and secondary mechanical hyperalgesia in lumbar axial deep tissues at L4/L5 and L1, respectively. In conclusion, our new rat model has considerable potential for providing novel insight on the pathobiology of mechanical LBP and for analgesic efficacy assessment of novel compounds.
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Affiliation(s)
- Arjun Muralidharan
- Centre for Integrated Preclinical Drug Development, The University of Queensland, BrisbaneQLD, Australia
| | - Thomas S W Park
- Centre for Integrated Preclinical Drug Development, The University of Queensland, BrisbaneQLD, Australia
| | - John T Mackie
- School of Veterinary Science, The University of Queensland, GattonQLD, Australia
| | - Luiz G S Gimenez
- Centre for Integrated Preclinical Drug Development, The University of Queensland, BrisbaneQLD, Australia
| | - Andy Kuo
- Centre for Integrated Preclinical Drug Development, The University of Queensland, BrisbaneQLD, Australia
| | | | | | - Maree T Smith
- Centre for Integrated Preclinical Drug Development, The University of Queensland, BrisbaneQLD, Australia.,School of Pharmacy, The University of Queensland, BrisbaneQLD, Australia
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10
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Liu DL, Wang X, Chu WG, Lu N, Han WJ, Du YK, Hu SJ, Bai ZT, Wu SX, Xie RG, Luo C. Chronic cervical radiculopathic pain is associated with increased excitability and hyperpolarization-activated current ( I h) in large-diameter dorsal root ganglion neurons. Mol Pain 2017; 13:1744806917707127. [PMID: 28587505 PMCID: PMC5466279 DOI: 10.1177/1744806917707127] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Cervical radiculopathic pain is a very common symptom that may occur with cervical
spondylosis. Mechanical allodynia is often associated with cervical radiculopathic pain
and is inadequately treated with current therapies. However, the precise mechanisms
underlying cervical radiculopathic pain-associated mechanical allodynia have remained
elusive. Compelling evidence from animal models suggests a role of large-diameter dorsal
root ganglion neurons and plasticity of spinal circuitry attached with Aβ fibers in
mediating neuropathic pain. Whether cervical radiculopathic pain condition induces plastic
changes of large-diameter dorsal root ganglion neurons and what mechanisms underlie these
changes are yet to be known. With combination of patch-clamp recording,
immunohistochemical staining, as well as behavioral surveys, we demonstrated that upon
chronic compression of C7/8 dorsal root ganglions, large-diameter cervical dorsal root
ganglion neurons exhibited frequent spontaneous firing together with hyperexcitability.
Quantitative analysis of hyperpolarization-activated cation current
(Ih) revealed that Ih was
greatly upregulated in large dorsal root ganglion neurons from cervical radiculopathic
pain rats. This increased Ih was supported by the enhanced
expression of hyperpolarization-activated, cyclic nucleotide-modulated channels subunit 3
in large dorsal root ganglion neurons. Blockade of Ih with
selective antagonist, ZD7288 was able to eliminate the mechanical allodynia associated
with cervical radiculopathic pain. This study sheds new light on the functional plasticity
of a specific subset of large-diameter dorsal root ganglion neurons and reveals a novel
mechanism that could underlie the mechanical allodynia associated with cervical
radiculopathy.
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Affiliation(s)
- Da-Lu Liu
- 1 Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, China.,2 Department of Radiation Medicine, Faculty of Preventive Medicine, Fourth Military Medical University, Xi'an, China
| | - Xu Wang
- 1 Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, China.,3 Research Center for Resource Polypeptide Drugs and College of Life Sciences, Yanan University, Yanan, China
| | - Wen-Guang Chu
- 1 Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, China
| | - Na Lu
- 1 Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, China.,4 ART Center, Northwest Women's and Children's Hospital, Xi'an, China
| | - Wen-Juan Han
- 1 Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, China
| | - Yi-Kang Du
- 5 The First Brigade, Fourth Military Medical University, Xi'an, China
| | - San-Jue Hu
- 1 Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, China
| | - Zhan-Tao Bai
- 3 Research Center for Resource Polypeptide Drugs and College of Life Sciences, Yanan University, Yanan, China
| | - Sheng-Xi Wu
- 1 Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, China
| | - Rou-Gang Xie
- 1 Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, China
| | - Ceng Luo
- 1 Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, China
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11
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Ibrahim SIA, Strong JA, Zhang JM. Mineralocorticoid Receptor, A Promising Target for Improving Management of Low Back Pain by Epidural Steroid Injections. ACTA ACUST UNITED AC 2016; 3:177-184. [PMID: 28956026 PMCID: PMC5611848 DOI: 10.24015/japm.2016.0023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
AIM OF REVIEW Low back pain is a major health problem in United States and worldwide. In this review, we aim to show that mineralocorticoid receptor (MR) activation has a critical role in the initiation of immune and inflammatory responses, which in turn can impact the effectiveness of the currently used steroids for epidural injections in low back pain management since most steroids activate MR in addition to the primary target, glucocorticoid receptor (GR). Moreover, we would like to determine some of the benefits of blocking the MR-induced negative effects. Overall, we propose a novel therapeutic approach for low back pain management by using a combination of a MR antagonist and a GR agonist in the epidural injections. METHOD We will first introduce the societal cost of low back pain and discuss how epidural steroid injections became a popular treatment for this condition. We will then describe several preclinical models used for the study of low back pain conditions and the findings with respect to the role of MR in the development of inflammatory low back pain. RECENT FINDINGS MR has pro-inflammatory effects in many tissues which can counteract the anti-inflammatory effects induced by GR activation. Blocking MR using the selective MR antagonist eplerenone can reduce pain and sensory neuron excitability in experimental models of low back pain. Moreover, combining the MR antagonist with clinically used steroids is more effective in reducing pain behaviors than using the steroids alone. SUMMARY MR antagonists are promising candidates to increase the effectiveness of currently used steroids. Since the activation of the MR is evident in preclinical models of low back pain, blocking its deleterious effects can be beneficial in managing inflammatory pain conditions.
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Affiliation(s)
- Shaimaa I A Ibrahim
- Pain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, USA.,Graduate Program in Molecular, Cellular, and Biochemical Pharmacology, University of Cincinnati, Cincinnati, USA
| | - Judith A Strong
- Pain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, USA
| | - Jun-Ming Zhang
- Pain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, USA
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12
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Obermair H, Janda M, Obermair A. Real-world surgical outcomes of a gelatin-hemostatic matrix in women requiring a hysterectomy: a matched case-control study. Acta Obstet Gynecol Scand 2016; 95:1008-14. [PMID: 27199208 DOI: 10.1111/aogs.12924] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 05/13/2016] [Indexed: 11/29/2022]
Abstract
INTRODUCTION The aim of this study was to compare adverse events and surgical outcomes of hysterectomy with or without use of a gelatin-hemostatic matrix (SURGIFLO(®) ). MATERIALS AND METHODS Prospective case-control study (Canadian Task Force classification II2) of total hysterectomy (Piver Type 1) provided by surgeons in Australia between November 2005 and May 2015. Data were collected via SurgicalPerformance, a web-based data project which aims to provide confidential feedback to surgeons about their surgical outcomes. Of 2440 records of women who received a hysterectomy, 1351 were eligible for these analyses; 107 received SURGIFLO(®) hemostatic matrix to prevent postoperative blood loss and 1244 did not. RESULTS Patients with or without SURGIFLO(®) differed in age, Charlson comorbidity index, and American Society of Anesthesiologists physical status classification system score (ASA), and also differed in clinical outcomes. After matching for patient's age and ASA at surgery, patients with and without SURGIFLO(®) had comparable baseline characteristics. Matched patients with and without SURGIFLO(®) had comparable clinical outcomes including risk of developing vault hematoma, return to the operating room, transfusion of red cells, surgical site infection (pelvis), readmission within 30 days and unplanned ICU admission. CONCLUSIONS In a sample matched by age and ASA, SURGIFLO(®) neither prevented nor caused additional adverse events in women undergoing hysterectomy. Surgeons used SURGIFLO(®) more commonly among women who were older, had more comorbidities and a higher ASA score. This indicates that it may be most useful in complicated surgery or cases.
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Affiliation(s)
- Helena Obermair
- School of Medicine, University of Notre Dame, Sydney, NSW, Australia
| | - Monika Janda
- Institute for Health and Biomedical Innovation, School of Public Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Andreas Obermair
- School of Medicine, The University of Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.,SurgicalPerformance Pty Ltd, Greenslopes Private Hospital, Brisbane, QLD, Australia
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Wang T, Hurwitz O, Shimada SG, Qu L, Fu K, Zhang P, Ma C, LaMotte RH. Chronic Compression of the Dorsal Root Ganglion Enhances Mechanically Evoked Pain Behavior and the Activity of Cutaneous Nociceptors in Mice. PLoS One 2015; 10:e0137512. [PMID: 26356638 PMCID: PMC4565551 DOI: 10.1371/journal.pone.0137512] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 08/18/2015] [Indexed: 11/29/2022] Open
Abstract
Radicular pain in humans is usually caused by intraforaminal stenosis and other diseases affecting the spinal nerve, root, or dorsal root ganglion (DRG). Previous studies discovered that a chronic compression of the DRG (CCD) induced mechanical allodynia in rats and mice, with enhanced excitability of DRG neurons. We investigated whether CCD altered the pain-like behavior and also the responses of cutaneous nociceptors with unmyelinated axons (C-fibers) to a normally aversive punctate mechanical stimulus delivered to the hairy skin of the hind limb of the mouse. The incidence of a foot shaking evoked by indentation of the dorsum of foot with an aversive von Frey filament (tip diameter 200 μm, bending force 20 mN) was significantly higher in the foot ipsilateral to the CCD surgery as compared to the contralateral side on post-operative days 2 to 8. Mechanically-evoked action potentials were electrophysiologically recorded from the L3 DRG, in vivo, from cell bodies visually identified as expressing a transgenically labeled fluorescent marker (neurons expressing either the receptor MrgprA3 or MrgprD). After CCD, 26.7% of MrgprA3+ and 32.1% MrgprD+ neurons exhibited spontaneous activity (SA), while none of the unoperated control neurons had SA. MrgprA3+ and MrgprD+ neurons in the compressed DRG exhibited, in comparison with neurons from unoperated control mice, an increased response to the punctate mechanical stimuli for each force applied (6, 20, 40, and 80 mN). We conclude that CCD produced both a behavioral hyperalgesia and an enhanced response of cutaneous C-nociceptors to aversive punctate mechanical stimuli.
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Affiliation(s)
- Tao Wang
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Neuroscience Center, Department of Anatomy, Histology and Embryology, Beijing, China
- Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Olivia Hurwitz
- Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Steven G. Shimada
- Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Lintao Qu
- Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins University, Baltimore, Maryland
| | - Kai Fu
- Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Pu Zhang
- Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Chao Ma
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Neuroscience Center, Department of Anatomy, Histology and Embryology, Beijing, China
- Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Robert H. LaMotte
- Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
- * E-mail:
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Xia T, Cui Y, Shi H, Ma Z, Gu X. The Effect of NR2B Subunit Palmitoylation at the Spinal Level After Chronic Dorsal Root Ganglia Compression in Rats. Anesth Analg 2014; 119:1208-14. [DOI: 10.1213/ane.0000000000000394] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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15
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Lin JH, Chiang YH, Chen CC. Lumbar radiculopathy and its neurobiological basis. World J Anesthesiol 2014; 3:162-173. [DOI: 10.5313/wja.v3.i2.162] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 04/10/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
Lumbar radiculopathy, a group of diseases in which the dorsal root ganglia (DRG) or dorsal roots are adversely affected by herniated discs or spinal stenosis, are clinically characterized by spontaneous and evoked types of pain. The pain is underpinned by various distinct pathophysiological mechanisms in the peripheral and central nervous systems. However, the diagnosis of lumbar radiculopathy is still unsatisfactory, because the association of the pain with the neurobiological basis of radiculopathy is largely unknown. Several animal models used to explore the underlying neurobiological basis of lumbar radiculopathy could be classified as mechanical, chemical, or both based on the component of injury. Mechanical injury elevates the intraneural pressure, reduces blood flow, and eventually establishes ischemia in the dorsal root and the DRG. Ischemia may induce ischemic pain and cause nerve damage or death, and the subsequent nerve damage or death may induce neuropathic pain. Chemical injury predominately induces inflammation surrounding the dorsal roots or DRG and consequent inflammatory mediators cause inflammatory pain. Furthermore, DRG neurons sensitized by inflammatory mediators are hypersensitive to innocuous mechanical force (stretch or compression) and responsible for mechanical allodynia in radiculopathy. As well, central sensitization in the spinal cord may play an important role in pain generation in lumbar radiculopathy. Increasing knowledge of pain-generating mechanisms and their translation into clinical symptoms and signs might allow for dissecting the mechanisms that operate in each patient. With precise clinical phenotypic characterization of lumbar radiculopathy and its connection to a specific underlying mechanism, we should be able to design optimal treatments for individuals. This review discusses the present knowledge of lumbar radiculopathy and proposes a novel mechanism-based classification.
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Zhang W, Liu Y, Zhao X, Gu X, Ma Z. The Effect of Intrathecal Administration TRPA1 Antagonists in a Rat Model of Neuropathic Pain. Anesth Analg 2014; 119:179-185. [DOI: 10.1213/ane.0000000000000179] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Activation of GRs-Akt-nNOs-NR2B signaling pathway by second dose GR agonist contributes to exacerbated hyperalgesia in a rat model of radicular pain. Mol Biol Rep 2014; 41:4053-61. [PMID: 24562683 DOI: 10.1007/s11033-014-3274-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 02/13/2014] [Indexed: 10/25/2022]
Abstract
Central Akt, neuronal nitric oxide synthase (nNOS) and N-methyl-D-aspartate receptor subunit 2B (NR2B) play key roles in the development of neuropathic pain. Here we investigate the effects of glucocorticoid receptors (GRs) on the expression and activation of spinal Akt, nNOS and NR2B after chronic compression of dorsal root ganglia (CCD). Thermal hyperalgesia test and mechanical allodynia test were used to measure rats after intrathecal injection of GR antagonist mifepristone or GR agonist dexamethasone for 21 days postoperatively. Expression of spinal Akt, nNOS, NR2B and their phosphorylation state after CCD was examined by western blot. The effects of intrathecal treatment with dexamethasone or mifepristone on nociceptive behaviors and the corresponding expression of Akt, nNOS and NR2B in spinal cord were also investigated. Intrathecal injection of mifepristone or dexamethasone inhibited PWMT and PWTL in CCD rats. However, hyperalgesia was induced by intrathecal injection of dexamethasone on days 12 to 14 after surgery. Treatment of dexamethasone increased the expression and phosphorylation levels of spinal Akt, nNOS, GR and NR2B time dependently, whereas administration of mifepristone downregulated the expression of these proteins significantly. GRs activated spinal Akt-nNOS/NR2B pathway play important roles in the development of neuropathic pain in a time-dependent manner.
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Gu X, Bo J, Zhang W, Sun X, Zhang J, Yang Y, Ma Z. Intrathecal administration of cyclic AMP response element-binding protein-antisense oligonucleotide attenuates neuropathic pain after peripheral nerve injury and decreases the expression of N-methyl-D-aspartic receptors in mice. Oncol Rep 2013; 30:391-8. [PMID: 23633027 DOI: 10.3892/or.2013.2437] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Accepted: 03/28/2013] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to determine whether the cAMP response element binding protein (CREB) contributes to neuropathic pain during development stage. Adult (7-8 weeks old) male C57BL/6 mice weighing 20-25 g were used. Intrathecal catheter implantation and chronic constriction of the sciatic nerve of the animals were performed. Western blotting and reverse transcription PCR experiments were carried out. Our study demonstrated that the expression of spinal NMDAR after peripheral nerve injury was modulated by central CREB. Chronic constriction nerve injury (CCI) in mice induced thermal hyperalgesia and mechanical allodynia. The increase of NR1 and NR2B subunits of the NMDAR was significantly diminished by intrathecal administration of the CREB antisense oligonucleotide against CREB and pCREB. Additionally, nociceptive behavior induced by CCI was attenuated by intrathecal administration of the CREB antisense oligonucleotide during the period of injection, and the above effects of relieving pain lasted at least 12 days following the last injection. Our results suggested that central functional pCREB may contribute to the development of neuropathic pain and regulate the expression of the NR1 and NR2B subunits of the NMDAR in the process.
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Affiliation(s)
- Xiaoping Gu
- Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical Department of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
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Strong JA, Xie W, Bataille FJ, Zhang JM. Preclinical studies of low back pain. Mol Pain 2013; 9:17. [PMID: 23537369 PMCID: PMC3617092 DOI: 10.1186/1744-8069-9-17] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Accepted: 03/18/2013] [Indexed: 12/12/2022] Open
Abstract
Chronic low back pain is a major cause of disability and health care costs. Current treatments are inadequate for many patients. A number of preclinical models have been developed that attempt to mimic aspects of clinical conditions that contribute to low back pain. These involve application of nucleus pulposus material near the lumbar dorsal root ganglia (DRG), chronic compression of the DRG, or localized inflammation of the DRG. These models, which are primarily implemented in rats, have many common features including behavioral hypersensitivity of the hindpaw, enhanced excitability and spontaneous activity of sensory neurons, and locally elevated levels of inflammatory mediators including cytokines. Clinically, epidural injection of steroids (glucocorticoids) is commonly used when more conservative treatments fail, but clinical trials evaluating these treatments have yielded mixed results. There are relatively few preclinical studies of steroid effects in low back pain models. One preclinical study suggests that the mineralocorticoid receptor, also present in the DRG, may have pro-inflammatory effects that oppose the activation of the glucocorticoid receptor. Although the glucocorticoid receptor is the target of anti-inflammatory steroids, many clinically used steroids activate both receptors. This could be one explanation for the limited effects of epidural steroids in some patients. Additional preclinical research is needed to address other possible reasons for limited efficacy of steroids, such as central sensitization or presence of an ongoing inflammatory stimulus in some forms of low back pain.
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Affiliation(s)
- Judith A Strong
- Pain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0531, USA
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Dorsal root ganglion compression as an animal model of sciatica and low back pain. Neurosci Bull 2012; 28:618-30. [PMID: 23054639 DOI: 10.1007/s12264-012-1276-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2012] [Accepted: 06/08/2012] [Indexed: 01/17/2023] Open
Abstract
As sciatica and low back pain are among the most common medical complaints, many studies have duplicated these conditions in animals. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The surgery is simple: after exposing the L4/L5 intervertebral foramina, stainless steel rods are implanted unilaterally, one rod for each vertebra, to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia - evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.
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Henderson CN. The basis for spinal manipulation: Chiropractic perspective of indications and theory. J Electromyogr Kinesiol 2012; 22:632-42. [DOI: 10.1016/j.jelekin.2012.03.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2011] [Revised: 03/15/2012] [Accepted: 03/20/2012] [Indexed: 12/21/2022] Open
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Sun YE, Peng L, Sun X, Bo J, Yang D, Zheng Y, Liu C, Zhu B, Ma Z, Gu X. Intrathecal injection of spironolactone attenuates radicular pain by inhibition of spinal microglia activation in a rat model. PLoS One 2012; 7:e39897. [PMID: 22768159 PMCID: PMC3387194 DOI: 10.1371/journal.pone.0039897] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Accepted: 05/28/2012] [Indexed: 01/28/2023] Open
Abstract
Background Microglia might play an important role in nociceptive processing and hyperalgesia by neuroinflammatory process. Mineralocorticoid receptor (MR) expressed on microglia might play a central role in the modulation of microglia activity. However the roles of microglia and MR in radicular pain were not well understood. This study sought to investigate whether selective MR antagonist spironolactone develop antinociceptive effects on radicular pain by inhibition neuroinflammation induced by spinal microglia activation. Results Radicular pain was produced by chronic compression of the dorsal root ganglia with SURGIFLO™. The expression of microglia, interleukin beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), NR1 subunit of the NMDA receptor (t-NR1), and NR1 subunit phosphorylated at Ser896 (p-NR1) were also markedly up-regulated. Intrathecal injection of spironolactone significantly attenuated pain behaviors as well as the expression of microglia, IL-1β, TNF-α, t-NR1, and p-NR1, whereas the production of IL-6 wasn’t affected. Conclusion These results suggest that intrathecal delivery spironolactone has therapeutic effects on radicular pain in rats. Decreasing the activation of glial cells, the production of proinflammatory cytokines and down-regulating the expression and phosphorylation of NMDA receptors in the spinal dorsal horn and dorsal root ganglia are the main mechanisms contributing to its beneficial effects.
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Affiliation(s)
- Yu-e Sun
- Department of Anaesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University, Nanjing, Jiangsu province, China
| | - Liangyu Peng
- Department of Anaesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University, Nanjing, Jiangsu province, China
| | - Xiaofeng Sun
- Department of Anaesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University, Nanjing, Jiangsu province, China
| | - Jinhua Bo
- Department of Anaesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University, Nanjing, Jiangsu province, China
| | - Dong Yang
- Department of Anaesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University, Nanjing, Jiangsu province, China
| | - Yaguo Zheng
- Department of Anaesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University, Nanjing, Jiangsu province, China
| | - Chenglong Liu
- Department of Anaesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University, Nanjing, Jiangsu province, China
| | - Beibei Zhu
- Department of Anaesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University, Nanjing, Jiangsu province, China
| | - Zhengliang Ma
- Department of Anaesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University, Nanjing, Jiangsu province, China
- * E-mail: (ZLM); (XPG)
| | - Xiaoping Gu
- Department of Anaesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University, Nanjing, Jiangsu province, China
- * E-mail: (ZLM); (XPG)
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Gu X, Peng L, Yang D, Ma Q, Zheng Y, Liu C, Zhu B, Song L, Sun X, Ma Z. The respective and interaction effects of spinal GRs and MRs on radicular pain induced by chronic compression of the dorsal root ganglion in the rat. Brain Res 2011; 1396:88-95. [PMID: 21550593 DOI: 10.1016/j.brainres.2011.04.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Revised: 04/05/2011] [Accepted: 04/07/2011] [Indexed: 01/02/2023]
Abstract
High levels of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are colocalized in the substantia gelatinosa. This indicates that the pain pathways appear to be under a strong regulation of these receptors. However, their respective effects on pain behaviors and their interaction remain unclear. Here we show that the nociceptive behaviors induced by chronic compression of the lumbar dorsal root ganglion (CCD) are attenuated by either GR agonist dexamethasone (4=2 μg>vehicle) or MR antagonist spironolactone (3 μg) administered intrathecally twice daily for postoperative days 2-4, whereas the GR antagonist mifepristone (2 μg) significantly exacerbated both mechanical hyperalgesia and thermal allodynia. Co-administration of spironolactone (3 μg) with dexamethasone (2 μg or 4 μg) twice daily on days 2-4 after CCD surgery produced positive synergistic effects. Moreover, different from intrathecally administered dexamethasone alone [no difference was found between two dose levels of dexamethasone (4 μg=2 μg)], dexamethasone suppresses mechanical allodynia and thermal hyperalgesia in a dose-dependent manner (4 μg>2 μg>vehicle) when combined with spironolactone (3 μg). These findings indicate that both central GRs and MRs play an important role in the regulation of pain behaviors and they have a perplexing interaction with each other. Spironolactone can enhance the analgesic effects of dexamethasone via complex mechanisms.
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Affiliation(s)
- XiaoPing Gu
- Department of Anaesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University, Jiangsu Province, China
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Amaya F, Samad TA, Barrett L, Broom DC, Woolf CJ. Periganglionic inflammation elicits a distally radiating pain hypersensitivity by promoting COX-2 induction in the dorsal root ganglion. Pain 2009; 142:59-67. [PMID: 19135800 PMCID: PMC2755568 DOI: 10.1016/j.pain.2008.11.013] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2007] [Revised: 11/20/2008] [Accepted: 11/21/2008] [Indexed: 12/19/2022]
Abstract
We have developed a model in which inflammation contiguous to and within a dorsal root ganglion (DRG) was generated by local application of complete Freund's adjuvant (CFA) to the L4 lumbar spinal nerve as it exits from the intervertebral foramen. The periganglionic inflammation (PGI) elicited a marked reduction in withdrawal threshold to mechanical stimuli and an increase in heat pain sensitivity in the ipsilateral hindpaw in the absence of any hindpaw inflammation. The pain sensitivity appeared within hours and lasted for a week. The PGI also induced a prominent increase in IL-1beta and TNF-alpha levels in the DRG and of cyclooxygenase-2 (COX-2) expression in neurons and satellite cells. A selective COX-2 inhibitor reduced the PGI-induced hyperalgesia. We also show that IL-1beta induces COX-2 expression and prostaglandin release in DRG neurons in vitro in a MAP kinase-dependent fashion. The COX-2 induction was prevented by ERK and p38 inhibitors. We conclude that periganglionic inflammation increases cytokine levels, including IL-1beta, leading to the transcription of COX-2 and prostaglandin production in the affected DRG, and thereby to the development of a dermatomally distributed pain hypersensitivity.
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Affiliation(s)
- Fumimasa Amaya
- Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, USA
- Department of Anesthesiology, Kyoto Prefectural University of Medicine, Japan
| | - Tarek A. Samad
- Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, USA
| | - Lee Barrett
- Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, USA
| | - Daniel C. Broom
- Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, USA
| | - Clifford J. Woolf
- Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, USA
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Dray A. New Horizons in Pharmacologic Treatment for Rheumatic Disease Pain. Rheum Dis Clin North Am 2008; 34:481-505. [DOI: 10.1016/j.rdc.2008.04.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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