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Neural Plasticity 2021Neuropathic pain is a common chronic pain, which is related to hypersensitivity to stimulus and greatly affects the quality of life of patients. Maladaptive gene changes...
BACKGROUND
Neuropathic pain is a common chronic pain, which is related to hypersensitivity to stimulus and greatly affects the quality of life of patients. Maladaptive gene changes and molecular signaling underlie the sensitization of nociceptive pathways. We previously found that the activation of microglial glucagon-like peptide 1 receptor (GLP-1R) could potently relieve formalin-, bone cancer-, peripheral nerve injury-, and diabetes-induced pain hypersensitivity. So far, little is known about how the gene profile changes upon the activation of GLP-1R signaling in the pathophysiology of neuropathic pain.
METHODS
Spinal nerve ligation (SNL) was performed to induce neuropathic pain in rats. Mechanical allodynia was assessed using von Frey filaments. The expression of IL-10, -endorphin, and -opioid receptor (MOR) was examined by real-time quantitative polymerase chain reaction (qPCR) and whole-cell recording. Measurements of cellular excitability of the substantia gelatinosa (SG) neurons by whole-cell recording were carried out. R packages of differential gene expression analysis based on the negative binomial distribution (DESeq2) and weighted correlation network analysis (WGCNA) were used to analyze differential gene expression and the correlated modules among GLP-1R clusters in neuropathic pain.
RESULTS
The GLP-1R agonist, exenatide, has an antiallodynic effect on neuropathic pain, which could be reversed by intrathecal injections of the microglial inhibitor minocycline. Furthermore, differential gene expression analysis (WGCNA) indicated that intrathecal injections of exenatide could reverse the abnormal expression of 591 genes in the spinal dorsal horn induced by nerve injury. WGCNA revealed 58 modules with a close relationship between the microglial GLP-1R pathway and features of nerve injuries, including pain, ligation, paw withdrawal latency (PWL), and anxiety. The brown module was identified as the highest correlated module, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that inflammatory responses were most correlated with PWL. To further unravel the changes of hyperalgesia-related neuronal electrophysiological activity mediated by microglia GLP-1 receptors, whole-cell recording identified that MOR agonism stimulated a robust outward current in the sham groups compared with the spinal nerve ligation (SNL) groups. This inhibitory effect on the SNL group was more sensitive than that of the sham group after bath application of -endorphin.
CONCLUSIONS
Our results further confirmed that the GLP-1R pathway is involved in alleviating pain hypersensitivity mediated by spinal microglia activation, and inflammatory responses were the most correlated pathway associated with PWL changes in response to exenatide treatment. We found that the identification of gene regulation in response to GLP-1R activation is an effective strategy for identifying new therapeutic targets for neuropathic pain. Investigation for the activation of spinal microglial GLP-1R which might ameliorate inflammatory responses through gene expression and structural changes is providing a potential biomarker in pain management.
Topics: Animals; Exenatide; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Inflammation Mediators; Injections, Spinal; Male; Microglia; Neuralgia; Rats; Rats, Wistar; Signal Transduction; Spinal Nerves
PubMed: 34512747
DOI: 10.1155/2021/9923537 -
Journal of Cellular and Molecular... Feb 2019Neuropathic pain is a well-known type of chronic pain caused by damage to the nervous system. Autophagy is involved in the development and/or progression of many...
Neuropathic pain is a well-known type of chronic pain caused by damage to the nervous system. Autophagy is involved in the development and/or progression of many diseases, including neuropathic pain. Emerging evidence suggests that metformin relieves neuropathic pain in several neuropathic pain models; however, metformin's cellular and molecular mechanism for pain relief remains unknown. In this study, we investigated the therapeutic effects of metformin on pain relief after spinal nerve ligation (SNL) and its underlying mechanism of autophagy regulation. Behavioural analysis, histological assessment, expression of c-Fos and molecular biological changes, as well as ultrastructural features, were investigated. Our findings showed that the number of autophagosomes and expression of autophagy markers, such as LC3 and beclin1, were increased, while the autophagy substrate protein p62, as well as the ubiquitinated proteins, were accumulated in the ipsilateral spinal cord. However, metformin enhanced the expression of autophagy markers, while it abrogated the abundance of p62 and ubiquitinated proteins. Blockage of autophagy flux by chloroquine partially abolished the apoptosis inhibition and analgesic effects of metformin on SNL. Taken together, these results illustrated that metformin relieved neuropathic pain through autophagy flux stimulation and provided a new direction for metformin drug development to treat neuropathic pain.
Topics: Animals; Autophagosomes; Autophagy; Behavior, Animal; Hypoglycemic Agents; Ligation; Male; Metformin; Neuralgia; Rats; Rats, Sprague-Dawley; Spinal Nerves; Surgical Procedures, Operative
PubMed: 30451370
DOI: 10.1111/jcmm.14033 -
British Journal of Anaesthesia Aug 1998
Review
Topics: Analgesia; Anesthetics, Local; Contraindications; Humans; Nerve Block; Spinal Nerves
PubMed: 9813528
DOI: 10.1093/bja/81.2.230 -
European Journal of Pain (London,... Jan 2019The term 'irritable nociceptor' was coined to describe neuropathic patients characterized by evoked hypersensitivity and preservation of primary afferent fibres....
BACKGROUND
The term 'irritable nociceptor' was coined to describe neuropathic patients characterized by evoked hypersensitivity and preservation of primary afferent fibres. Oxcarbazepine is largely ineffectual in an overall patient population, but has clear efficacy in a subgroup with the irritable nociceptor profile. We examine whether neuropathy in rats induced by spinal nerve injury shares overlapping pharmacological sensitivity with the irritable nociceptor phenotype using drugs that target sodium channels.
METHODS
In vivo electrophysiology was performed in anaesthetized spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range (WDR) neurones in the ventral posterolateral thalamus (VPL) and dorsal horn.
RESULTS
In neuropathic rats, spontaneous activity in the VPL was substantially attenuated by spinal lidocaine, an effect that was absent in sham rats. The former measure was in part dependent on ongoing peripheral activity as intraplantar lidocaine also reduced aberrant spontaneous thalamic firing. Systemic oxcarbazepine had no effect on wind-up of dorsal horn neurones in sham and SNL rats. However, in SNL rats, oxcarbazepine markedly inhibited punctate mechanical-, dynamic brush- and cold-evoked neuronal responses in the VPL and dorsal horn, with minimal effects on heat-evoked responses. In addition, oxcarbazepine inhibited spontaneous activity in the VPL. Intraplantar injection of the active metabolite licarbazepine replicated the effects of systemic oxcarbazepine, supporting a peripheral locus of action.
CONCLUSIONS
We provide evidence that ongoing activity in primary afferent fibres drives spontaneous thalamic firing after spinal nerve injury and that oxcarbazepine through a peripheral mechanism exhibits modality-selective inhibitory effects on sensory neuronal processing.
SIGNIFICANCE
The inhibitory effects of lidocaine and oxcarbazepine in this rat model of neuropathy resemble the clinical observations in the irritable nociceptor patient subgroup and support a mechanism-based rationale for bench-to-bedside translation when screening novel drugs.
Topics: Action Potentials; Animals; Ligation; Male; Neuralgia; Neurons; Nociceptors; Oxcarbazepine; Peripheral Nervous System Diseases; Phenotype; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Spinal Nerves; Thalamus; Ventral Thalamic Nuclei; Voltage-Gated Sodium Channel Blockers
PubMed: 30091265
DOI: 10.1002/ejp.1300 -
Experimental Physiology Aug 2018What is the central question of this study? Is spontaneous activity (SA) in L4 dorsal root ganglion (DRG) neurons induced by L5 spinal nerve axotomy associated with...
Membrane potential oscillations are not essential for spontaneous firing generation in L4 Aβ-afferent neurons after L5 spinal nerve axotomy and are not mediated by HCN channels.
NEW FINDINGS
What is the central question of this study? Is spontaneous activity (SA) in L4 dorsal root ganglion (DRG) neurons induced by L5 spinal nerve axotomy associated with membrane potential oscillations in these neurons, and if so, are these membrane oscillations mediated by HCN channels? What is the main finding and its importance? Unlike injured L5 DRG neurons, which have been shown to be incapable of firing spontaneously without membrane potential oscillations, membrane potential oscillations are not essential for SA generation in conducting 'uninjured' L4 neurons, and they are not mediated by HCN channels. These findings suggest that the underlying cellular mechanisms of SA in injured and 'uninjured' DRG neurons induced by spinal nerve injury are distinct.
ABSTRACT
The underlying cellular and molecular mechanisms of peripheral neuropathic pain are not fully understood. However, preclinical studies using animal models suggest that this debilitating condition is driven partly by aberrant spontaneous activity (SA) in injured and uninjured dorsal root ganglion (DRG) neurons, and that SA in injured DRG neurons is triggered by subthreshold membrane potential oscillations (SMPOs). Here, using in vivo intracellular recording from control L4-DRG neurons, and ipsilateral L4-DRG neurons in female Wistar rats that had previously undergone L5 spinal nerve axotomy (SNA), we examined whether conducting 'uninjured' L4-DRG neurons in SNA rats exhibit SMPOs, and if so, whether such SMPOs are associated with SA in those L4 neurons, and whether they are mediated by hyperpolarization-activated cyclic nucleotide gated (HCN) channels. We found that 7 days after SNA: (a) none of the control A- or C-fibre DRG neurons showed SMPOs or SA, but 50%, 43% and 0% of spontaneously active cutaneous L4 Aβ-low threshold mechanoreceptors, Aβ-nociceptors and C-nociceptors exhibited SMPOs, respectively, in SNA rats with established neuropathic pain behaviors; (b) neither SMPOs nor SA in L4 Aβ-neurons was suppressed by blocking HCN channels with ZD7288 (10 mg kg , i.v.); and (c) there is a tendency for female rats to show greater pain hypersensitivity than male rats. These results suggest that SMPOs are linked to SA only in some of the conducting L4 Aβ-neurons, that such oscillations are not a prerequisite for SA generation in those L4 A- or C-fibre neurons, and that HCN channels are not involved in their electrogenesis.
Topics: Action Potentials; Animals; Axotomy; Female; Ganglia, Spinal; Hyperalgesia; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Membrane Potentials; Neuralgia; Neurons, Afferent; Pain Measurement; Rats; Rats, Wistar; Spinal Nerves
PubMed: 29860719
DOI: 10.1113/EP087013 -
Analytical Cellular Pathology... 2019Neuropathic pain not only affects individual life quality but also increases economic burden for the society. Treatment to alleviate neuropathic pain is required.
BACKGROUND
Neuropathic pain not only affects individual life quality but also increases economic burden for the society. Treatment to alleviate neuropathic pain is required.
METHODOLOGY
Fifty rats were randomly assigned into sham, spinal nerve ligation, and three treatment groups with different doses of Tempol (100, 200, and 300 mg/kg, respectively), with 10 rats in each group. A neuropathic pain model was created with spinal nerve L5 and L6 ligation. Mechanical allodynia and thermal hyperalgesia were tested preoperatively (day 0) and postoperatively (days 1, 3, 5, and 7). Spinal cord levels of nitric oxide, as well as activities of nitric oxide synthase and acetylcholinesterase, were tested in postoperative day 7.
RESULTS
Compared with rats in the spinal nerve ligation group, rats in Tempol treatment groups had decreased responses to mechanical pain and cold plate stimulations. A high dose of Tempol produced more attenuating effects. The level of nitric oxide and activity of nitric oxide synthase were also decreased with Tempol treatments, whereas no significant changes were observed in the activity of acetylcholinesterase.
CONCLUSIONS
Tempol attenuated an experimental rat model with neuropathic pain by inhibiting nitric oxide production.
Topics: Animals; Cyclic N-Oxides; Male; Neuralgia; Neuroprotective Agents; Nitric Oxide; Rats; Rats, Sprague-Dawley; Spin Labels; Spinal Nerves
PubMed: 31223559
DOI: 10.1155/2019/8253850 -
Medicine Feb 2021MR tractography of the lumbosacral plexus (LSP) is challenging due to the difficulty of acquiring high quality data and accurately estimating the neuronal tracts. We... (Comparative Study)
Comparative Study
MR tractography of the lumbosacral plexus (LSP) is challenging due to the difficulty of acquiring high quality data and accurately estimating the neuronal tracts. We proposed an algorithm for an accurate visualization and assessment of the major LSP bundles using the segmentation of the cauda equina as seed points for the initial starting area for the fiber tracking algorithm.Twenty-six healthy volunteers underwent MRI examinations on a 3T MR scanner using the phased array coils with optimized measurement protocols for diffusion-weighted images and coronal T2 weighted 3D short-term inversion recovery sampling perfection with application optimized contrast using varying flip angle evaluation sequences used for LSP fiber reconstruction and MR neurography (MRN).The fiber bundles reconstruction was optimized in terms of eliminating the muscle fibers contamination using the segmentation of cauda equina, the effects of the normalized quantitative anisotropy (NQA) and angular threshold on reconstruction of the LSP. In this study, the NQA parameter has been used for fiber tracking instead of fractional anisotropy (FA) and the regions of interest positioning was precisely adjusted bilaterally and symmetrically in each individual subject.The diffusion data were processed in individual L3-S2 nerve fibers using the generalized Q-sampling imaging algorithm. Data (mean FA, mean diffusivity, axial diffusivity and radial diffusivity, and normalized quantitative anisotropy) were statistically analyzed using the linear mixed-effects model. The MR neurography was performed in MedINRIA and post-processed using the maximum intensity projection method to demonstrate LSP tracts in multiple planes.FA values significantly decreased towards the sacral region (P < .001); by contrast, mean diffusivity, axial diffusivity, radial diffusivity and NQA values significantly increased towards the sacral region (P < .001).Fiber tractography of the LSP was feasible in all examined subjects and closely corresponded with the nerves visible in the maximum intensity projection images of MR neurography. Usage of NQA instead of FA in the proposed algorithm enabled better separation of muscle and nerve fibers.The presented algorithm yields a high quality reconstruction of the LSP bundles that may be helpful both in research and clinical practice.
Topics: Adult; Algorithms; Anisotropy; Cauda Equina; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Female; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Lumbosacral Plexus; Lumbosacral Region; Magnetic Resonance Imaging; Male; Spinal Nerves
PubMed: 33578590
DOI: 10.1097/MD.0000000000024646 -
Current Pain and Headache Reports Sep 2014Cervicogenic headache (CGH) is defined as referred pain from various cervical structures innervated by the upper three cervical spinal nerves. Such structures are... (Review)
Review
Cervicogenic headache (CGH) is defined as referred pain from various cervical structures innervated by the upper three cervical spinal nerves. Such structures are potential pain generators, and include the atlanto-occipital joint, atlantoaxial joint, C2-3 zygapophysial joint, C2-3 intervertebral disc, cervical myofascial trigger points, as well as the cervical spinal nerves. Various interventional techniques, including cervical epidural steroid injection (CESI), have been proposed to treat this disorder. And while steroids administered by cervical epidural injection have been used in clinical practice to provide anti-inflammatory and analgesic effects that may alleviate pain in patients with CGH, the use of CESI in the diagnosis and treatment of CGH remains controversial. This article describes the neuroanatomy, neurophysiology, and classification of CGH as well as a review of the available literature describing CESI as treatment for this debilitating condition.
Topics: Anesthetics, Local; Cervical Vertebrae; Diagnosis, Differential; Humans; Injections, Epidural; Neck Injuries; Nerve Block; Pain Measurement; Patient Selection; Post-Traumatic Headache; Quality of Life; Spinal Nerves; Steroids; Treatment Outcome
PubMed: 25091129
DOI: 10.1007/s11916-014-0442-3 -
Molecular Pain Jul 2011Several studies have investigated the involvement of nitric oxide (NO) in acute and chronic pain using mice lacking a single NO synthase (NOS) gene among the three...
BACKGROUND
Several studies have investigated the involvement of nitric oxide (NO) in acute and chronic pain using mice lacking a single NO synthase (NOS) gene among the three isoforms: neuronal (nNOS), inducible (iNOS) and endothelial (eNOS). However, the precise role of NOS/NO in pain states remains to be determined owing to the substantial compensatory interactions among the NOS isoforms. Therefore, in this study, we used mice lacking all three NOS genes (n/i/eNOS-/-mice) and investigated the behavioral phenotypes in a series of acute and chronic pain assays.
RESULTS
In a model of tissue injury-induced pain, evoked by intraplantar injection of formalin, both iNOS-/-and n/i/eNOS-/-mice exhibited attenuations of pain behaviors in the second phase compared with that in wild-type mice. In a model of neuropathic pain, nerve injury-induced behavioral and cellular responses (tactile allodynia, spinal microglial activation and Src-family kinase phosphorylation) were reduced in n/i/eNOS-/-but not iNOS-/-mice. Tactile allodynia after nerve injury was improved by acute pharmacological inhibition of all NOSs and nNOS. Furthermore, in MG-5 cells (a microglial cell-line), interferon-γ enhanced NOSs and Mac-1 mRNA expression, and the Mac-1 mRNA increase was suppressed by L-NAME co-treatment. Conversely, the NO donor, sodium nitroprusside, markedly increased mRNA expression of Mac-1, interleukin-6, toll-like receptor 4 and P2X4 receptor.
CONCLUSIONS
Our results provide evidence that the NOS/NO pathway contributes to behavioral pain responses evoked by tissue injury and nerve injury. In particular, nNOS may be important for spinal microglial activation and tactile allodynia after nerve injury.
Topics: Animals; Behavior, Animal; Gene Expression Regulation; Gene Knockout Techniques; Hyperalgesia; Inflammation; Interferon-gamma; Interleukin-6; Macrophage-1 Antigen; Male; Mice; Microglia; Neuralgia; Nitric Oxide; Nitric Oxide Synthase; RNA, Messenger; Receptors, Purinergic P2X4; Spinal Cord; Spinal Nerves; Temperature; Toll-Like Receptor 4; src-Family Kinases
PubMed: 21756313
DOI: 10.1186/1744-8069-7-50 -
Veterinary Research Communications Jun 2022Hamsters are often chosen as companion animals but are also a group of animals frequently subjected to laboratory tests. As there are no scientific publications...
Hamsters are often chosen as companion animals but are also a group of animals frequently subjected to laboratory tests. As there are no scientific publications providing information on the anatomical architecture of the brachial plexus of the Djungarian hamster, this study analyses the structure of this part of the nervous system of this species. It is important to know the details of this structure not only for cognitive reasons, but also due to the increasing clinical significance of rodents, which are often used in scientific research. The study was conducted on 55 specimens. Like in humans, the brachial plexus of the Djungarian hamster has three trunks. The following individual nerves innervating the thoracic limb of the Djungarian hamster: the radial nerve, median nerve, ulnar nerve, musculocutaneous nerve, axillary nerve, suprascapular nerve, thoracodorsal nerve, cranial pectoral nerves, caudal pectoral nerve, lateral thoracic nerve, long thoracic nerve, and subscapular nerves. Similarly to other mammals of this order, the brachial plexus of the Djungarian hamster ranges widely (C5-T1). However, its nerves are formed from different ventral branches of the spinal nerves than in other mammals.
Topics: Animals; Brachial Plexus; Cricetinae; Forelimb; Phodopus; Thoracic Nerves
PubMed: 34984572
DOI: 10.1007/s11259-021-09877-1