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Neuromodulation : Journal of the... Jan 2023Complex regional pain syndrome (CRPS) is a chronic debilitating disease characterized by sensory abnormalities. Spinal cord stimulation (SCS) is an effective therapy for... (Randomized Controlled Trial)
Randomized Controlled Trial
Allodynia, Hyperalgesia, (Quantitative) Sensory Testing and Conditioned Pain Modulation in Patients With Complex Regional Pain Syndrome Before and After Spinal Cord Stimulation Therapy.
OBJECTIVES
Complex regional pain syndrome (CRPS) is a chronic debilitating disease characterized by sensory abnormalities. Spinal cord stimulation (SCS) is an effective therapy for CRPS, but few studies have investigated the effects of SCS therapy on sensory characteristics. Therefore, this study investigated the effect of SCS on allodynia, hyperalgesia, electrical quantitative sensory testing (QST) parameters, and conditioned pain modulation (CPM) effect.
MATERIALS AND METHODS
This study is part of a multicenter randomized controlled trial (ISRCTN 36655259). Patients with CRPS in one extremity and eligible for SCS were included. The outcome parameters allodynia (symptom and sign), hyperalgesia (symptom), sensory thresholds with QST, CPM effect, and pain scores were tested before and after three months of SCS (40-Hz tonic SCS). Both the CRPS-affected extremity and the contralateral, clinically unaffected extremity were used to test three sensory thresholds with electrical QST: current perception threshold (CPT), pain perception threshold (PPT), and pain tolerance threshold (PTT). The PTT also was used as a test stimulus for the CPM paradigm both before and after the conditioning ice-water test. Nonparametric testing was used for all statistical analyses.
RESULTS
In total, 31 patients were included for analysis. Pain, allodynia (sign and symptom), and hyperalgesia (symptom) were all significantly reduced after SCS therapy. On the unaffected side, none of the QST thresholds (CPT, PPT, and PTT) was significantly altered after SCS therapy. However, the CPT on the CRPS-affected side was significantly increased after SCS therapy. A CPM effect was present both before and after SCS.
CONCLUSIONS
Standard 40-Hz tonic SCS significantly reduces pain, hyperalgesia, and allodynia in patients with CRPS. These findings suggest that SCS therapy should not be withheld from patients who suffer from allodynia and hyperalgesia, which contradicts previous findings derived from retrospective analysis and animal research. ISRCTN Registry: The ISRCTN registration number for the study is ISRCTN 36655259.
Topics: Humans; Hyperalgesia; Spinal Cord Stimulation; Retrospective Studies; Pain Threshold; Complex Regional Pain Syndromes; Chronic Disease; Spinal Cord
PubMed: 36050204
DOI: 10.1016/j.neurom.2022.06.009 -
Cells Sep 2022Physical activity-based rehabilitative interventions represent the main treatment concept for people suffering from spinal cord injury (SCI). The role such interventions... (Review)
Review
Physical activity-based rehabilitative interventions represent the main treatment concept for people suffering from spinal cord injury (SCI). The role such interventions play in the relief of neuropathic pain (NP) states is emerging, along with underlying mechanisms resulting in SCI-induced NP (SCI-NP). Animal models have been used to investigate the benefits of activity-based interventions (ABI), such as treadmill training, wheel running, walking, swimming, and bipedal standing. These activity-based paradigms have been shown to modulate inflammatory-related alterations as well as induce functional and structural changes in the spinal cord gray matter circuitry correlated with pain behaviors. Thus far, the research available provides an incomplete picture of the cellular and molecular pathways involved in this beneficial effect. Continued research is essential for understanding how such interventions benefit SCI patients suffering from NP and allow the development of individualized rehabilitative therapies. This article reviews preclinical studies on this specific topic, goes over mechanisms involved in SCI-NP in relation to ABI, and then discusses the effectiveness of different activity-based paradigms as they relate to different forms, intensity, initiation times, and duration of ABI. This article also summarizes the mechanisms of respective interventions to ameliorate NP after SCI and provides suggestions for future research directions.
Topics: Animals; Gray Matter; Hyperalgesia; Motor Activity; Neuralgia; Spinal Cord Injuries
PubMed: 36231048
DOI: 10.3390/cells11193087 -
International Journal of Molecular... Apr 2022Low back pain (LBP) management is an important clinical issue. Inadequate LBP control has consequences on the mental and physical health of patients. Thus, acquiring new...
Low back pain (LBP) management is an important clinical issue. Inadequate LBP control has consequences on the mental and physical health of patients. Thus, acquiring new information on LBP mechanism would increase the available therapeutic tools. Resveratrol is a natural compound with many beneficial effects. In this study, we investigated the role of resveratrol on behavioral changes, inflammation and oxidative stress induced by LBP. Ten microliters of Complete Freund's adjuvant (CFA) was injected in the lumbar intervertebral disk of Sprague Dawley rats to induce degeneration, and resveratrol was administered daily. Behavioral analyses were performed on day zero, three, five and seven, and the animals were sacrificed to evaluate the molecular pathways involved. Resveratrol administration alleviated hyperalgesia, motor disfunction and allodynia. Resveratrol administration significantly reduced the loss of notochordal cells and degenerative changes in the intervertebral disk. From the molecular point of view, resveratrol reduced the 5th/6th lumbar (L5-6) spinal activation of the WNT pathway, reducing the expression of WNT3a and cysteine-rich domain frizzled (FZ)8 and the accumulation of cytosolic and nuclear β-catenin. Moreover, resveratrol reduced the levels of TNF-α and IL-18 that are target genes strictly downstream of the WNT/β-catenin pathway. It also showed important anti-inflammatory activities by reducing the activation of the NFkB pathway, the expression of iNOS and COX-2, and the levels of PGE2 in the lumbar spinal cord. Moreover, resveratrol reduced the oxidative stress associated with inflammation and pain, as shown by the observed reduced lipid peroxidation and increased GSH, SOD, and CAT activities. Therefore, resveratrol administration controlled the WNT/β-catenin pathway and the related inflammatory and oxidative alterations, thus alleviating the behavioral changes induced by LBP.
Topics: Animals; Humans; Hyperalgesia; Inflammation; Low Back Pain; Rats; Rats, Sprague-Dawley; Resveratrol; Wnt Signaling Pathway; beta Catenin
PubMed: 35456908
DOI: 10.3390/ijms23084092 -
Brain and Behavior Mar 2022Brachial plexus avulsion significantly increased brain-derived neurotrophic factor (BDNF) release in the spinal cord. Here we investigated the involvement of the...
INTRODUCTION
Brachial plexus avulsion significantly increased brain-derived neurotrophic factor (BDNF) release in the spinal cord. Here we investigated the involvement of the BDNF-TrkB-KCC2 pathway in neuropathic pain caused by BPA injury. We hypothesized that activation of BDNF-TrkB may inhibit neuronal excitability by downregulating KCC2 to maintain a high intracellular Cl-concentration. We established a neuropathic pain rat model by avulsion of the lower trunk brachial plexus, and investigated the effects of the TrkB-specific antibody K-252a on the expression of BDNF, TrkB, and KCC2.
METHODS
We randomly divided 40 male SD rats into four groups. In the brachial plexus avulsion group, C8-T1 roots were avulsed from the spinal cord at the lower trunk level. In the K252a group, 5uL K252a was applied intrathecally daily for three days after avulsion. In the sham surgery group, expose only and without damage. The control group did not undergo any treatment. Mechanical hyperalgesia and cold allodynia were analyzed by electronic pain measuring instrument and acetone spray method at different time points on days 1, 3, 7, 10, 14, and 21 after surgery. At 21 days after surgery, the expression of BDNF and TrkB in dorsal horn neurons and GFAP in astrocytes were detected by immunohistochemistry at the C5-T1 segment of the spinal cord. The expression levels of BDNF, TrkB, and KCC2 in the C5-T1 spinal cord were measured by Western Blot at 7 and 21 days.
RESULTS
Mechanical hyperalgesia and cold allodynia were significantly reduced in the K252a group compared with the brachial plexus avulsion group. Compared with the BPA group, BDNF, TrkB and GFAP were significantly decreased in the K252a group at 21 days after treatment by immunohistochemical test. In the WB test, the expressions of BDNF and TrkB in the K252a group were quantitatively detected to be decreased, while the expression of KCC2 was increased, which was obvious at 7 and 21 days.
CONCLUSION
BDNF-TrkB-KCC2 pathway can significantly relieve neuropathic pain after BPA, and is a potential target for the treatment of neuropathic pain.
Topics: Animals; Brachial Plexus; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Female; Hyperalgesia; Male; Neuralgia; Rats; Rats, Sprague-Dawley; Symporters
PubMed: 35106976
DOI: 10.1002/brb3.2464 -
The Journal of Neuroscience : the... Jul 2021Systemic treatment with resiniferatoxin (RTX) induces small-fiber sensory neuropathy by damaging TRPV1-expressing primary sensory neurons and causes distinct thermal...
Systemic treatment with resiniferatoxin (RTX) induces small-fiber sensory neuropathy by damaging TRPV1-expressing primary sensory neurons and causes distinct thermal sensory impairment and tactile allodynia, which resemble the unique clinical features of postherpetic neuralgia. However, the synaptic plasticity associated with RTX-induced tactile allodynia remains unknown. In this study, we found that RTX-induced neuropathy is associated with α2δ-1 upregulation in the dorsal root ganglion (DRG) and increased physical interaction between α2δ-1 and GluN1 in the spinal cord synaptosomes. RNAscope hybridization showed that RTX treatment significantly increased α2δ-1 expression in DRG neurons labeled with calcitonin gene-related peptide, isolectin B4, NF200, and tyrosine hydroxylase. Electrophysiological recordings revealed that RTX treatment augmented the frequency of miniature excitatory postsynaptic currents (mEPSCs) and the amplitude of evoked EPSCs in spinal dorsal horn neurons, and these effects were reversed by blocking NMDA receptors with AP-5. Inhibiting α2δ-1 with gabapentin, genetically ablating α2δ-1, or targeting α2δ-1-bound NMDA receptors with α2δ-1Tat peptide largely normalized the baseline frequency of mEPSCs and the amplitude of evoked EPSCs potentiated by RTX treatment. Furthermore, systemic treatment with memantine or gabapentin and intrathecal injection of AP-5 or Tat-fused α2δ-1 C terminus peptide reversed allodynia in RTX-treated rats and mice. In addition, RTX-induced tactile allodynia was attenuated in α2δ-1 knock-out mice and in mice in which GluN1 was conditionally knocked out in DRG neurons. Collectively, our findings indicate that α2δ-1-bound NMDA receptors at presynaptic terminals of sprouting myelinated afferent nerves contribute to RTX-induced potentiation of nociceptive input to the spinal cord and tactile allodynia. Postherpetic neuralgia (PHN), associated with shingles, is a distinct form of neuropathic pain commonly seen in elderly and immunocompromised patients. The synaptic plasticity underlying touch-induced pain hypersensitivity in PHN remains unclear. Using a nonviral animal model of PHN, we found that glutamatergic input from primary sensory nerves to the spinal cord is increased via tonic activation of glutamate NMDA receptors. Also, we showed that α2δ-1 (encoded by ), originally considered a calcium channel subunit, serves as an auxiliary protein that promotes activation of presynaptic NMDA receptors and pain hypersensitivity. This new information advances our understanding of the molecular mechanism underlying PHN and suggests new strategies for treating this painful condition.
Topics: Animals; Calcium Channels, L-Type; Diterpenes; Ganglia, Spinal; Glutamic Acid; Hyperalgesia; Male; Mice; Neuralgia; Neuralgia, Postherpetic; Neurotoxins; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sensory Receptor Cells; Up-Regulation
PubMed: 34252037
DOI: 10.1523/JNEUROSCI.0303-21.2021 -
Current Neuropharmacology 2023Brachial plexus avulsion (BPA) animally involves the separation of spinal nerve roots themselves and the correlative spinal cord segment, leading to formidable...
BACKGROUND
Brachial plexus avulsion (BPA) animally involves the separation of spinal nerve roots themselves and the correlative spinal cord segment, leading to formidable neuropathic pain of the upper limb.
METHODS
The right seventh cervical (C7) ventral and dorsal roots were avulsed to establish a neuropathic pain model in rats. After operation, rats were treated with quercetin (QCN) by intragastric administration for 1 week. The effects of QCN were evaluated using mechanical allodynia tests and biochemical assay kits.
RESULTS
QCN treatment significantly attenuated the avulsion-provoked mechanical allodynia, elevated the levels of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) and total antioxidant capacity (TAC) in the C7 spinal dorsal horn. In addition, QCN administration inhibited the activations of macrophages, microglia and astrocytes in the C6 dorsal root ganglion (DRG) and C6-8 spinal dorsal horn, as well as attenuated the release of purinergic 2X (P2X) receptors in C6 DRG. The molecular mechanism underlying the above alterations was found to be related to the suppression of the PKC/MAPK/NOX signal pathway. To further study the anti-oxidative effects of QCN, we applied QCN on the HO-induced BV-2 cells , and the results attested that QCN significantly ameliorated the HO-induced ROS production in BV-2 cells, inhibited the HO-induced activation of PKC/MAPK/NOX pathway.
CONCLUSION
Our study for the first time provided evidence that QCN was able to attenuate pain hypersensitivity following the C7 spinal root avulsion in rats, and the molecular mechanisms involve the reduction of both neuro-inflammatory infiltration and oxidative stress via suppression of P2X receptors and inhibition of the activation of PKC/MAPK/NOX pathway. The results indicate that QCN is a natural compound with great promise worthy of further development into a novel therapeutic method for the treatment of BPA-induced neuropathic pain.
Topics: Rats; Animals; Hyperalgesia; Quercetin; Hydrogen Peroxide; Brachial Plexus; Neuralgia; Spinal Cord Dorsal Horn; Oxidative Stress
PubMed: 37533160
DOI: 10.2174/1570159X21666230802144940 -
The Journal of Pain Apr 2023Youth with complex regional pain syndrome (CRPS) commonly experience mechanical allodynia and disability. Assessment of mechanical allodynia is typically binary (present...
Clinical Assessment of Mechanical Allodynia in Youth With Complex Regional Pain Syndrome: Development and Preliminary Validation of the Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense).
Youth with complex regional pain syndrome (CRPS) commonly experience mechanical allodynia and disability. Assessment of mechanical allodynia is typically binary (present or absent), making it difficult to assess the quality and degree of mechanical allodynia before and after treatment. This study developed and validated the Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense) to provide an easy way for rehabilitation clinicians to evaluate mechanical allodynia before and after intensive interdisciplinary pain treatment. The 6 Pedi-Sense items demonstrated adequate internal consistency reliability (CR) at admission (CR = .956) and discharge (CR = .973), reasonably fit the hypothesized linear model of stimulus intensity (P < .0001), and significantly loaded onto a single latent factor, mechanical allodynia (P < .0001), at admission and discharge. Pedi-Sense scores significantly correlated with disability (r = .40; P = .004) and pain catastrophizing (r = .33; P = .017) at admission. The Pedi-Sense appeared responsive to intervention as participants' total scores improved by 1.44 points (95% CI: .72, 2.15) after IIPT interventions that included daily tactile desensitization. However, test-retest and interrater reliability and the specific contribution of desensitization treatment to the overall success of multi-modal pain rehabilitation still needs to be evaluated. PERSPECTIVE: This article presents the development and preliminary validation of a novel clinical assessment of static and dynamic mechanical allodynia. The Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense) allows rehabilitation clinicians to easily evaluate mechanical allodynia at the bedside with minimal training and simple equipment to guide desensitization treatment in clinical settings.
Topics: Humans; Child; Adolescent; Hyperalgesia; Reproducibility of Results; Pain; Complex Regional Pain Syndromes; Pain Measurement
PubMed: 36592646
DOI: 10.1016/j.jpain.2022.12.006 -
Molecules (Basel, Switzerland) Jan 2021Oxaliplatin is a platinum derivative chemotherapeutic drug widely used against cancers, but even a single treatment can induce a severe allodynia that requires treatment...
Oxaliplatin is a platinum derivative chemotherapeutic drug widely used against cancers, but even a single treatment can induce a severe allodynia that requires treatment interruption and dose diminution. The rhizome of roscoe (, ginger), has been widely used in traditional medicine to treat various diseases causing pain; however, its effect against oxaliplatin-induced neuropathic pain has never been assessed. In mice, a single oxaliplatin (6 mg/kg, i.p.) treatment induced significant cold and mechanical allodynia. Cold and mechanical allodynia were assessed by acetone drop and von Frey filament tests, respectively. Water extracts of (100, 300, and 500 mg/kg, p.o.) significantly attenuated both cold and mechanical allodynia induced by oxaliplatin. Intrathecal pre-treatment with the antagonist 5-HT (NAN-190, i.t., 1 μg), but not with the antagonist 5-HT (ketanserin, i.t., 1 μg), significantly blocked the analgesic effect of against both cold and mechanical allodynia. However, 5-HT antagonist (MDL-72222, i.t., 15 μg) administration only blocked the anti-allodynic effect of against cold allodynia. Real-time PCR analysis demonstrated that significantly increased the mRNA expression of the spinal 5-HT receptor that was downregulated after oxaliplatin injection. These results suggest that may be a viable treatment option for oxaliplatin-induced neuropathic pain.
Topics: Analgesics; Animals; Gene Expression Regulation; Zingiber officinale; Hyperalgesia; Mice; Neuralgia; Oxaliplatin; Plant Extracts; Receptor, Serotonin, 5-HT1A; Rhizome
PubMed: 33494465
DOI: 10.3390/molecules26030548 -
Biomedicine & Pharmacotherapy =... Oct 2022Fibromyalgia (FM) is an idiopathic disorder characterized by generalized pain and associated symptoms such as depression and anxiety. Cannabis sativa shows different...
Fibromyalgia (FM) is an idiopathic disorder characterized by generalized pain and associated symptoms such as depression and anxiety. Cannabis sativa shows different pharmacological activities, such as analgesic, anti-inflammatory, neuroprotective, and immunomodulatory. Associated with this, the use of an oil with low concentrations of THC can reduce the psychomimetic adverse effects of the plant. Therefore, the present study aimed to evaluate the analgesic effect of broad-spectrum cannabis oil with low THC concentration in an experimental model of FM. Mechanical hyperalgesia, thermal allodynia, depressive- and anxious-related behavior, and locomotor activity were evaluated after reserpine (0.25 mg/kg; injected subcutaneously (s.c.) once daily for three consecutive days) administration. Our results showed that oral administration of broad-spectrum cannabis oil (0.1, 1, and 3 mg/kg, p.o.) in a single dose on the 4th day inhibited mechanical hyperalgesia and thermal allodynia induced by reserpine. Relevantly, treatment during four days with broad-spectrum cannabis oil (0.1 mg/kg, p.o.) reduced mechanical hyperalgesia 1 h after reserpine administration. Intraplantar treatment with cannabis oil significantly reversed mechanical and heat thermal nociception induced by reserpine injection. Interestingly, spinal and supraspinal administration of broad-spectrum cannabis oil completely inhibited mechanical hyperalgesia and thermal sensitivity induced by reserpine. The repeated cannabis oil administration, given daily for 14 days, markedly mitigated the mechanical and thermal sensitivity during the FM model, and its reduced depressive-like behavior induced by reserpine. In summary, broad-spectrum cannabis oil is an effective alternative to reverse the reserpine-induced fibromyalgia model.
Topics: Analgesics; Animals; Cannabis; Disease Models, Animal; Dronabinol; Fibromyalgia; Hyperalgesia; Mice; Reserpine
PubMed: 35988425
DOI: 10.1016/j.biopha.2022.113552 -
Annals of Neurology Jan 2021Cortical spreading depression (SD) is an intense depolarization underlying migraine aura. Despite the weight of evidence linking SD to the pain phase of migraine,...
OBJECTIVE
Cortical spreading depression (SD) is an intense depolarization underlying migraine aura. Despite the weight of evidence linking SD to the pain phase of migraine, controversy remains over a causal role of SD in cephalgia because of the invasive nature of previous SD induction methods. To overcome this problem, we used a novel minimally invasive optogenetic SD induction method and examined the effect of SD on behavior.
METHODS
Optogenetic SD was induced as a single event or repeatedly every other day for 2 weeks. End points, including periorbital and hindpaw mechanical allodynia, mouse grimace, anxiety, and working memory, were examined in male and female mice.
RESULTS
A single SD produced bilateral periorbital mechanical allodynia that developed within 1 hour and resolved within 2 days. Sumatriptan prevented periorbital allodynia when administered immediately after SD. Repeated SDs also produced bilateral periorbital allodynia that lasted 4 days and resolved within 2 weeks after the last SD. In contrast, the hindpaw withdrawal thresholds did not change after repeated SDs suggesting that SD-induced allodynia was limited to the trigeminal region. Moreover, repeated SDs increased mouse grimace scores 2 days after the last SD, whereas a single SD did not. Repeated SDs also increased thigmotaxis scores as a measure of anxiety. In contrast, neither single nor repeated SDs affected visuospatial working memory. We did not detect sexual dimorphism in any end point.
INTERPRETATION
Altogether, these data show a clinically congruent causal relationship among SD, trigeminal pain, and anxiety behavior, possibly reflecting SD modulation of hypothalamic, thalamic, and limbic mechanisms. ANN NEUROL 2021;89:99-110.
Topics: Animals; Anxiety; Behavior, Animal; Cortical Spreading Depression; Depression; Disease Models, Animal; Hyperalgesia; Mice, Transgenic; Optogenetics
PubMed: 33016466
DOI: 10.1002/ana.25926