GPER/β-Alanine Positive Interaction in The Dorsal Root Ganglion Uncovers Potential Mechanisms: Mediating Continuous Neuronal Sensitisation and Neuroinflammation Responses in Neuropathic Pain

Abstract Background: The pathogenesis of neuropathic pain and the reasons for the prolonged unhealing are still unknown. Increasing evidence suggests that estrogen sex differences play a role in pain sensitivity, but few studies focused on the role of estrogen receptor which maybe an important molecular component contributing to peripheral pain transduction. We aimed to investigate the impact of oestrogen receptors in nociceptive neuronal response in the dorsal root ganglion (DRG) and spinal dorsal horn using a spared nerve injury (SNI) rat model of chronic pain. Methods: We used a class of estrogen receptors antagonists and agonists intrathecal (i.t.) administrated to male rats with SNI or normal rats to identify the main receptor. Moreover, we applied genes identified through genomic metabolic analysis to determine the key metabolism point and elucidate potential mechanisms mediating continuous neuronal sensitisation and neuroinflammation responses in neuropathic pain. The excitability of DRG neurons was detected using the patch clamp technique. Immunohistochemistry, Western blotting, qPCR and behavioral testing were used to assess the expressions, cellular distributions, and actions of main receptor and its related signaling molecules.Results: Increasing the expression and function of G protein-coupled estrogen receptor (GPER), but not estrogen receptor-α (ERα) and estrogen receptor-β (ERβ), in the DRG, but not the dorsal spinal cord, contributed to SNI-induced neuronal sensitisation. Inhibiting GPER expression in the DRG alleviated SNI-induced pain behaviours and neuroinflammation by downregulating IL-1β and IL-6 expression as well as restoring GABAα2 expression simultaneously. Additionally, the positive interaction between GPER and β-alanine, β-alanine accumulation enhances pain sensation and promotes chronic pain development. Conclusion: GPER activation in the DRG causes a positive interaction of β-alanine with IL-1β and IL-6 expression and represses GABAα2 involved in post-SNI neuropathic pain development. Blocking GPER and eliminating β-alanine in the DRG may prevent neuropathic pain development.

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Dorsal Root Ganglion Stimulation for the Management of Chronic Neuropathic Pain: A Retrospective Case Series during Four Years follow-up in a Single Center

The Open Pain Journal ◽

10.2174/1876386302013010035 ◽

2020 ◽

Vol 13 (1) ◽

pp. 35-41

Author(s):

Alfonso Papa ◽

Elisabetta Saracco ◽

Maria Teresa Di Dato ◽

Pietro Buonavolontà ◽

Anna Maria Salzano ◽

...

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Dorsal Root Ganglion ◽

Data Collection ◽

Dorsal Root ◽

Case Series ◽

Chronic Neuropathic Pain ◽

Neuropathic Pain Syndrome

Objectives: The dorsal root ganglion (DRG) is involved in the transduction of pain signals to the central nervous system (CNS) and undergoes a number of physiopathological changes during chronic pain. The purpose of this data collection was to evaluate the long-term safety and efficacy of DRG stimulation for the treatment of chronic pain and its impact on functional aspects. Materials and Methods: Forty-four subjects with non-reactive chronic neuropathic pain syndrome were implanted with DRG stimulation. Patients were evaluated at baseline as well as at 15, and 30 days, and at 3, 6, 12, 24, 36 and 48 months after medical intervention/surgery using the Visual Analogic Scale (VAS), which measures pain intensity, and the Oswestry Scale, for the estimation of disability (ODI). Results: After four years of simulation, VAS and ODI showed a statistically significant reduction throughout the follow-up period. The average pain relief obtained after 48 months of treatment was 74.1% ± 3.4. Conclusion: The results of this data collection demonstrate the feasibility of DRG stimulation, the correspondence between the clinical indications at the DRG implant and what is commonly found in the literature on this technique.(18,20) Patients defined as clinical responders to DRG stimulation and so implanted with definitive IPG showed a sustained and long term efficacy. Eight patients had previously been implanted with a traditional SCS without any clinically relevant efficacy; they were then explained for unsatisfactory results. Six of them (75%) were later implanted with DRG, with long-term effectiveness. Another advantage of this therapy is the absence of positional effects and lead migration. The adverse events proved to be independent of the anatomical level of insertion; moreover, this series of cases show a lower incidence of lead migration than reported in the literature. In summary, DRGs have been ignored for too long, probably due to the technical difficulty of reaching their deep, almost extra-spinal anatomical position.

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Quantitative Sensory Testing of Spinal Cord and Dorsal Root Ganglion Stimulation in Chronic Pain Patients

Neuromodulation Technology at the Neural Interface ◽

10.1111/ner.13329 ◽

2021 ◽

Author(s):

Vishwanath Sankarasubramanian ◽

Srinivas Chiravuri ◽

Ehsan Mirzakhalili ◽

Carlos J. Anaya ◽

John Ryan Scott ◽

...

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Dorsal Root Ganglion ◽

Dorsal Root ◽

Quantitative Sensory Testing ◽

Sensory Testing ◽

Chronic Pain Patients ◽

Pain Patients

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Role of TRPV4-P2X7 Pathway in Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion

Neurochemical Research ◽

10.1007/s11064-021-03352-8 ◽

2021 ◽

Author(s):

Xiaohua Fan ◽

Chuanwei Wang ◽

Junting Han ◽

Xinli Ding ◽

Shaocan Tang ◽

...

Keyword(s):

Neuropathic Pain ◽

Dorsal Root Ganglion ◽

Dorsal Root

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A Prospective Analysis of Neuromonitoring for Confirmation of Lead Placement in Dorsal Root Ganglion Stimulation

Operative Neurosurgery ◽

10.1093/ons/opx172 ◽

2017 ◽

Vol 14 (6) ◽

pp. 654-660 ◽

Cited By ~ 9

Author(s):

Steven M Falowski ◽

Andreas Dianna

Keyword(s):

Neuropathic Pain ◽

Dorsal Root Ganglion ◽

Dorsal Root ◽

Evoked Potential ◽

Somatosensory Evoked Potential ◽

Prospective Analysis ◽

Awake Patient ◽

Chronic Neuropathic Pain ◽

Lead Placement

Abstract BACKGROUND Dorsal root ganglion stimulation is a neuromodulation therapy used for chronic neuropathic pain. Typically, patients are awakened intraoperatively to confirm adequate placement. OBJECTIVE To determine whether neuromonitoring can confirm placement in an asleep patient. METHODS This is a prospective analysis of 12 leads placed in 6 patients. Lead confirmation was confirmed by awake intraoperative testing, as well as asleep testing utilizing neuromonitoring. Patients were used as their own control. Sensory and motor thresholds for each patient with awake and asleep neuromonitoring testing were recorded. Intraoperative impedance and postoperative programming were also recorded. RESULTS In each patient, paresthesias were generated prior to motor contractions in the awake patient. For each patient, somatosensory evoked potential responses were present after lowering below the dropout threshold of electromyogram responses with neuromonitoring. There were varying degrees of separation in the thresholds that did not appear to be consistent across level or diagnosis. Smaller degrees of separation between thresholds during awake testing also held true in the asleep patient. This was further confirmed with postoperative programming. Impedances did not alter the separation in thresholds or amount of stimulation required for responses. One patient was combative during awake testing, and therefore motor thresholds were not obtained. This same patient was determined to have a ventral placement, confirmed with awake and asleep neuromonitoring testing. CONCLUSION This series demonstrates that the proposed neuromonitoring protocol can be used in an asleep patient to assure proper positioning of the dorsal root ganglion electrode in the dorsal foramen by generating somatosensory evoked potential responses in the absence of electromyogram responses.

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Intervertebral foramen injection of plerixafor attenuates neuropathic pain after chronic compression of the dorsal root ganglion: Possible involvement of the down-regulation of Nav1.8 and Nav1.9

European Journal of Pharmacology ◽

10.1016/j.ejphar.2021.174322 ◽

2021 ◽

pp. 174322

Author(s):

Fei Yang ◽

Yi-Qing Zou ◽

Min Li ◽

Wen-Jun Luo ◽

Guo-Zhong Chen ◽

...

Keyword(s):

Neuropathic Pain ◽

Dorsal Root Ganglion ◽

Dorsal Root ◽

Intervertebral Foramen ◽

Down Regulation

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Dorsal Root Ganglion Neuron Types and Their Functional Specialization

The Oxford Handbook of the Neurobiology of Pain ◽

10.1093/oxfordhb/9780190860509.013.4 ◽

2018 ◽

pp. 127-155 ◽

Cited By ~ 3

Author(s):

Edward C. Emery ◽

Patrik Ernfors

Keyword(s):

Chronic Pain ◽

Dorsal Root Ganglion ◽

Sensory Neurons ◽

Dorsal Root ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Drg Neurons ◽

Low Threshold

Primary sensory neurons of the dorsal root ganglion (DRG) respond and relay sensations that are felt, such as those for touch, pain, temperature, itch, and more. The ability to discriminate between the various types of stimuli is reflected by the existence of specialized DRG neurons tuned to respond to specific stimuli. Because of this, a comprehensive classification of DRG neurons is critical for determining exactly how somatosensation works and for providing insights into cell types involved during chronic pain. This article reviews the recent advances in unbiased classification of molecular types of DRG neurons in the perspective of known functions as well as predicted functions based on gene expression profiles. The data show that sensory neurons are organized in a basal structure of three cold-sensitive neuron types, five mechano-heat sensitive nociceptor types, four A-Low threshold mechanoreceptor types, five itch-mechano-heat–sensitive nociceptor types and a single C–low-threshold mechanoreceptor type with a strong relation between molecular neuron types and functional types. As a general feature, each neuron type displays a unique and predicable response profile; at the same time, most neuron types convey multiple modalities and intensities. Therefore, sensation is likely determined by the summation of ensembles of active primary afferent types. The new classification scheme will be instructive in determining the exact cellular and molecular mechanisms underlying somatosensation, facilitating the development of rational strategies to identify causes for chronic pain.

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