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The Korean Journal of Parasitology Aug 2022Vincristine (VCR) is a chemotherapeutic agent widely used in treatment of malignancies. However, VCR has a limitation in use since it commonly causes a painful...
Vincristine (VCR) is a chemotherapeutic agent widely used in treatment of malignancies. However, VCR has a limitation in use since it commonly causes a painful neuropathy (VCR-induced peripheral neuropathy, VIPN). Inflammatory cytokines secreted by immune cells such as macrophages can exacerbate allodynia and hyperalgesia, because inhibiting the inflammatory response is a treatment target for VIPN. In this study, we investigated whether Trichinella spiralis, a widely studied helminth for its immunomodulatory abilities, can alleviate VCR-induced allodynia. Von Frey test showed that T. spiralis infection improved mechanical allodynia at 10 days after VCR injection. We further observed whether the difference was due to mitigated axon degeneration, but no significant difference between the groups in axonal degeneration in sciatic nerves and intra-epidermal nerve fibers was found. Conversely, we observed that number of infiltrated macrophages was decreased in the sciatic nerves of the T. spiralis infected mice. Moreover, treatment of T. spiralis excretory-secretory products caused peritoneal macrophages to secrete decreased level of IL-1β. This study suggests that T. spiralis can relieve VCR-induced mechanical allodynia by suppressing neuroinflammation and that application of controllable degree of helminth may prove beneficial for VIPN treatment.
Topics: Animals; Hyperalgesia; Mice; Neuroinflammatory Diseases; Trichinella; Trichinella spiralis; Trichinellosis; Vincristine
PubMed: 36041486
DOI: 10.3347/kjp.2022.60.4.247 -
Journal of Obstetrics and Gynaecology... May 2020This study sought to characterize central sensitization further among women with chronic pelvic pain by identifying temporal summation using a cotton-tipped applicator... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This study sought to characterize central sensitization further among women with chronic pelvic pain by identifying temporal summation using a cotton-tipped applicator test that can be used at the bedside.
METHOD
A total of 36 women (18 with chronic pain and allodynia; 18 without pain) were recruited. Both groups were randomly assigned to receive 3 strokes of a benign stimulus on the abdomen at differing frequencies: 10, 30, or 100 seconds. Each group included 6 women. Pain was assessed using a rating scale of 1 to 10. Data were analyzed using the multivariate approach to repeated measures analysis of variance.
RESULTS
The pattern of pain scores differed significantly between women with and without chronic pain (P = 0.002). Women with chronic pelvic pain and allodynia showed a statistically significant increase in pain with successive strokes of the cotton-tipped applicator (P = 0.012 for stroke 1 vs. 2, P = 0.026 for stroke 2 vs. 3, and P = 0.005 for stroke 1 vs. 3).
CONCLUSION
Women with chronic pelvic pain and allodynia showed significant worsening of pain with successive strokes of a cotton-tipped applicator. This finding indicates that pain wind-up and central sensitization are present in women with chronic pelvic pain and allodynia. Identification of summation is further evidence of neuroplasticity, which is helpful in innovative therapies for chronic pelvic pain.
Topics: Adult; Chronic Pain; Female; Humans; Hyperalgesia; Pain Measurement; Pelvic Pain; Postsynaptic Potential Summation; Sensitivity and Specificity
PubMed: 31882288
DOI: 10.1016/j.jogc.2019.09.012 -
Neuropharmacology May 2022Chronic social isolation generates a persistent state of stress associated with obesity along with some neuro-endocrine disorders and central behavioral sequelae (eg...
Chronic social isolation generates a persistent state of stress associated with obesity along with some neuro-endocrine disorders and central behavioral sequelae (eg anxiety, depression, aggression, and allodynia). In this study, we evaluated the effect of social isolation on body weight, depressive- and anxious-aggressive-like behavior, as well as on phenotypic changes of adipocytes from visceral adipose tissue of control (group-housed) or socially isolated (single-housed) male mice. The effect of treatment with pentadecyl-2-oxazoline (PEA-OXA), a natural alpha2 antagonist and histamine H3 protean partial agonist, on these alterations was also evaluated. Single or group-housed mice treated with vehicle or PEA-OXA underwent body weight, mechanical allodynia, anxious-, depressive- and aggressive-like behavior measurements. Proliferation rate, apoptosis, senescence, expression of fat lineage genes, lipid droplets and proinflammatory cytokines were measured on white adipose tissue adipocytes from group- or single-housed mice. Single housed mice developed weight gain, mechanical allodynia at the von Frey test, aggressiveness in the resident intruder test, depression- and anxiety-like behavior in the tail suspension and hole drop tests, respectively. Single housed mice receiving PEA-OXA showed a general resolution of both, physical-metabolic and behavioral alterations associated with social isolation. Furthermore, adipocytes from the adipose tissue of socially isolated mice showed an evident inflamed phenotype (i.e. a reduced rate of proliferation, apoptosis, senescence, and ROS hyper-production together with an increased expression of IL-1β, IL-10, IL-17, and TNF-α and a decrease of IL-6). The treatment with PEA-OXA on adipocytes from single housed mice produced a protective/anti-inflammatory phenotype with an increased expression of brown adipose tissue biomarker. This study confirms that persistent stress caused by social isolation predisposes to obesity and neuropsychiatric disorders. PEA-OXA, through its multi-target activity on alpha2 adrenoceptor and histamine H3 receptors, which have recently aroused great interest in the neuropsychiatric field, reduces weight gain, systemic pro-inflammatory state, allodynia, and affective disorders associated with social isolation.
Topics: Adipose Tissue; Animals; Body Weight; Hyperalgesia; Male; Mice; Obesity; Oxazoles; Social Isolation; Weight Gain
PubMed: 35157898
DOI: 10.1016/j.neuropharm.2022.108978 -
Journal of Translational Medicine Aug 2023Peripheral nerve injury can cause neuroinflammation and neuromodulation that lead to mitochondrial dysfunction and neuronal apoptosis in the dorsal root ganglion (DRG)...
BACKGROUND
Peripheral nerve injury can cause neuroinflammation and neuromodulation that lead to mitochondrial dysfunction and neuronal apoptosis in the dorsal root ganglion (DRG) and spinal cord, contributing to neuropathic pain and motor dysfunction. Hyperbaric oxygen therapy (HBOT) has been suggested as a potential therapeutic tool for neuropathic pain and nerve injury. However, the specific cellular and molecular mechanism by which HBOT modulates the development of neuropathic pain and motor dysfunction through mitochondrial protection is still unclear.
METHODS
Mechanical and thermal allodynia and motor function were measured in rats following sciatic nerve crush (SNC). The HBO treatment (2.5 ATA) was performed 4 h after SNC and twice daily (12 h intervals) for seven consecutive days. To assess mitochondrial function in the spinal cord (L2-L6), high-resolution respirometry was measured on day 7 using the OROBOROS-O2k. In addition, RT-PCR and Immunohistochemistry were performed at the end of the experiment to assess neuroinflammation, neuromodulation, and apoptosis in the DRG (L3-L6) and spinal cord (L2-L6).
RESULTS
HBOT during the early phase of the SNC alleviates mechanical and thermal hypersensitivity and motor dysfunction. Moreover, HBOT modulates neuroinflammation, neuromodulation, mitochondrial stress, and apoptosis in the DRG and spinal cord. Thus, we found a significant reduction in the presence of macrophages/microglia and MMP-9 expression, as well as the transcription of pro-inflammatory cytokines (TNFa, IL-6, IL-1b) in the DRG and (IL6) in the spinal cord of the SNC group that was treated with HBOT compared to the untreated group. Notable, the overexpression of the TRPV1 channel, which has a high Ca permeability, was reduced along with the apoptosis marker (cleaved-Caspase3) and mitochondrial stress marker (TSPO) in the DRG and spinal cord of the HBOT group. Additionally, HBOT prevents the reduction in mitochondrial respiration, including non-phosphorylation state, ATP-linked respiration, and maximal mitochondrial respiration in the spinal cord after SNC.
CONCLUSION
Mitochondrial dysfunction in peripheral neuropathic pain was found to be mediated by neuroinflammation and neuromodulation. Strikingly, our findings indicate that HBOT during the critical period of the nerve injury modulates the transition from acute to chronic pain via reducing neuroinflammation and protecting mitochondrial function, consequently preventing neuronal apoptosis in the DRG and spinal cord.
Topics: Rats; Animals; Peripheral Nerve Injuries; Rats, Sprague-Dawley; Neuroinflammatory Diseases; Neuralgia; Hyperalgesia; Sciatic Nerve; Spinal Cord; Mitochondria
PubMed: 37582750
DOI: 10.1186/s12967-023-04414-x -
Clinical Neurology and Neurosurgery Sep 2022Cutaneous allodynia (CA) is a common symptom in migraine. Its incidence is more frequent in the chronic migraine (CM). CA usually occurs during pain attacks. However, it...
OBJECTIVE
Cutaneous allodynia (CA) is a common symptom in migraine. Its incidence is more frequent in the chronic migraine (CM). CA usually occurs during pain attacks. However, it can also be interictal and its frequency and severity seem to be correlated with the duration of the disease. Several quantitative sensory testing (QST) studies have revealed variable results about mechanical and thermal allodynia accompanying migraine. This study aimed to investigate the effects of CA and onabotulinumtoxinA (BoNT-A) injection on the thermal thresholds measured by QST in patients with CM. The effects of BoNT-A on headaches, CA, and other accompanying symptoms of migraine were also evaluated.
METHODS
Single BoNT-A injections were performed in 22 female cases (mean age: 38.1 ± 7.2 years) with CM. Patients were evaluated at 1-7 days before, 28-35, and 84-91 days after the injection. The 22 healthy women in the control group (mean age: 36.6 ± 7.6 years) were examined once. Headache and its characteristics, medication intake, allodynia, presence of anxiety, and depression symptoms were evaluated through relevant scales. The heat (HDT) and cold (CDT) detection thresholds on the forehead and hand were measured bilaterally with QST. The presence of brush allodynia for patients was examined by applying a 4 × 4 gauze pad over the same areas.
RESULTS
The patients in the CM group had migraine for an average of 22.5 ± 6.1 years and CM for 6.1 ± 3.2 years. The average number of painful days per month was 22.1 ± 4.0 days. All the patients had migraine attacks with CA (mean 5.6/month). The average allodynia symptom checklist (ASC-12) score was 7.8 ± 6.2. Thermal thresholds measured in the patients with CM were similar to those of the controls. Thermal thresholds did not show significant differences between the symptomatic and the asymptomatic sides at the last migraine attack. There was also no correlation between the allodynia revealed by the physical examination and the thermal thresholds detected by QST. The ASC-12 score decreased significantly with BoNT-A injection (p = 0.030), but no significant change was observed in thermal thresholds after this treatment.
CONCLUSION
There was no significant correlation between CA and thermal thresholds. BoNT-A was successful in relieving headache and other associated symptoms, including CA, but had no significant effect on QST parameters.
Topics: Adult; Botulinum Toxins, Type A; Female; Headache; Humans; Hyperalgesia; Middle Aged; Migraine Disorders; Pain
PubMed: 35792471
DOI: 10.1016/j.clineuro.2022.107357 -
Neuroscience Letters Aug 2022Mechanical allodynia has been studied in chronic naltrexone-treated people (N.T.P.) and rats (N.T.R.). After persistent naltrexone administration, patients acquired...
Mechanical allodynia has been studied in chronic naltrexone-treated people (N.T.P.) and rats (N.T.R.). After persistent naltrexone administration, patients acquired static and dynamic mechanical allodynia, as measured by von Frey filament (vFf) and brush stimulations. Pregabalin and levodopa administrations in N.T.P. significantly reduced allodynic behaviour, albeit these molecules did not completely stop it. As evidenced by the deployment of the vFf, subchronic treatment with Naltrexone delivered peripherally or intrathecally induced allodynic behaviour in rats. Increased expressions of two pain markers, pERK1/2 and PKCγ, in the spinal dorsal horn laminae were associated with naltrexone-induced allodynic behaviour. After vFf stimulation, pERK1/2 expression was substantially higher (p < 0.001) in superficial spinal dorsal horn laminae than in non-stimulated or naive non-stimulated rats. In addition, when compared to control rats, N.T.R. showed a substantial (p < 0.001) increase in PKCγ expression. PKCγ expression was found to be strong in lamina IIi and laminae III-IV. A cellular mechanism is proposed for the naltrexone effect. In both people and rats, Naltrexone induces static mechanical allodynia, according to this study.
Topics: Animals; Humans; Hyperalgesia; Naltrexone; Pain; Rats; Rats, Sprague-Dawley; Spinal Cord Dorsal Horn
PubMed: 35901909
DOI: 10.1016/j.neulet.2022.136816 -
Headache Nov 2020This study sought to investigate the relationship between allodynia, psychological variables, and disability among individuals with migraine.
OBJECTIVE
This study sought to investigate the relationship between allodynia, psychological variables, and disability among individuals with migraine.
BACKGROUND
A growing body of research views migraine as a condition of stress-related physiological dysregulation. Cutaneous allodynia is one manifestation of this dysregulation and affects a majority of individuals with migraine, though it is typically discussed in the context of headache pathophysiology. Stress, like allodynia, is implicated in the development of central sensitization and migraine progression. However, the contributions of stress and related psychological factors in allodynia and resulting disability remain largely unknown.
METHODS
A cross-sectional study at a Southern U.S. university queried young adults with migraine regarding headache symptoms, disability, allodynia symptom frequency, and psychological variables using validated measures. Relations among allodynia and psychological variables of relevance were examined, including the association between allodynia and disability after controlling for pain severity. Subsequently, we assessed whether stress mediated the relationship between allodynia and disability.
RESULTS
The final sample consisted of 147 young adults (87.8% [129/147] female, mean age = 19.0 ± 2.4) with an average headache frequency of 9.9 days per month (SD = 5.9). Increases in allodynia showed small associations with increases in stress, (r = 0.26, P = .001), fear of pain (r = 0.22, P = .008), and headache-related disability (r = 0.18, P = .003); and a small association with reduced self-efficacy (r = -0.16, P = .049). Allodynia significantly predicted disability even after controlling for pain severity (∆R = 0.02, P = .040), and the allodynia-disability relationship was mediated by stress (point estimate = 0.10, 95% CI [0.02-0.21]), such that as allodynia severity increased, stress increased and subsequent disability worsened.
CONCLUSIONS
This study establishes meaningful relationships between allodynia and psychological variables of importance to headache self-management and adaptive coping. Allodynia exerts some effect on disability independent of pain itself, and this relationship is partially driven by stress. This study highlights the potential role of the stress response among those with allodynia, and further research is needed to determine if migraine interventions that target maladaptive stress responses may reduce disability by impeding the feedforward loop of allostatic load.
Topics: Adolescent; Adult; Comorbidity; Cross-Sectional Studies; Disabled Persons; Female; Functional Status; Humans; Hyperalgesia; Male; Migraine Disorders; Severity of Illness Index; Stress, Psychological; Young Adult
PubMed: 33169381
DOI: 10.1111/head.14012 -
Pharmacological Reports : PR Aug 2023For many chemotherapy patients peripheral neuropathy is a debilitating side effect. Mitragyna speciosa (kratom) contains the alkaloid mitragynine (MG), which produces...
Cannabidiol and mitragynine exhibit differential interactive effects in the attenuation of paclitaxel-induced mechanical allodynia, acute antinociception, and schedule-controlled responding in mice.
BACKGROUND
For many chemotherapy patients peripheral neuropathy is a debilitating side effect. Mitragyna speciosa (kratom) contains the alkaloid mitragynine (MG), which produces analgesia in multiple preclinical pain models. In humans, anecdotal reports suggest cannabidiol (CBD) may enhance kratom-related analgesia. We examined the interactive activity of MG and CBD in a mouse chemotherapy-induced peripheral neuropathy (CIPN) model. We also examined MG + CBD in acute antinociception and schedule-controlled responding assays, as well as examined underlying receptor mechanisms.
METHODS
Male and female C57BL/6J mice received a cycle of intraperitoneal (ip) paclitaxel injections (cumulative dose 32 mg/kg). The von Frey assay was utilized to assess CIPN allodynia. In paclitaxel-naïve mice, schedule-controlled responding for food was conducted under a fixed ratio (FR)-10, and hot plate antinociception was examined.
RESULTS
MG dose-relatedly attenuated CIPN allodynia (ED 102.96 mg/kg, ip), reduced schedule-controlled responding (ED 46.04 mg/kg, ip), and produced antinociception (ED 68.83 mg/kg, ip). CBD attenuated allodynia (ED 85.14 mg/kg, ip) but did not decrease schedule-controlled responding or produce antinociception. Isobolographic analysis revealed 1:1, 3:1 MG + CBD mixture ratios additively attenuated CIPN allodynia. All combinations decreased schedule-controlled responding and produced antinociception. WAY-100635 (serotonin 5-HT1A receptor antagonist) pretreatment (0.01 mg/kg, ip) antagonized CBD anti-allodynia. Naltrexone (pan opioid receptor antagonist) pretreatment (0.032 mg/kg, ip) antagonized MG anti-allodynia and acute antinociception but produced no change in MG-induced decreased schedule-controlled behavior. Yohimbine (α receptor antagonist) pretreatment (3.2 mg/kg, ip) antagonized MG anti-allodynia and produced no change in MG-induced acute antinociception or decreased schedule-controlled behavior.
CONCLUSIONS
Although more optimization is needed, these data suggest CBD combined with MG may be useful as a novel CIPN therapeutic.
Topics: Mice; Humans; Male; Female; Animals; Paclitaxel; Cannabidiol; Hyperalgesia; Mice, Inbred C57BL; Peripheral Nervous System Diseases; Disease Models, Animal; Pain
PubMed: 37243887
DOI: 10.1007/s43440-023-00498-w -
Drug Design, Development and Therapy 2023The aim of this study was to investigate the effect of Zhiqiao Gancao decoction (ZQGCD) on hyperalgesia in lumbar disc herniation (LDH) and its mechanism.
PURPOSE
The aim of this study was to investigate the effect of Zhiqiao Gancao decoction (ZQGCD) on hyperalgesia in lumbar disc herniation (LDH) and its mechanism.
METHODS
The potential mechanism of ZQGCD's therapeutic effect on LDH was investigated through network pharmacology, which involved screening the targets of eight components that were absorbed into the bloodstream. The effects of CCR2 inhibitors and ZQGCD-containing serum on the excitability of the CCL2/CCR2 signaling pathway and dorsal root ganglion neurons (DRGn) were investigated in vitro. The effects of CCR2 inhibitors and ZQGCD on the expression of the CCL2/CCR2 signaling pathway and ASIC3 in the rat intervertebral disc and dorsal root ganglion (DRG), the degree of disc degeneration, the threshold of foot retreat, and the latency of foot retreat in LDH rats were examined in vivo. The binding affinities and interaction modes between CCR2 and the components absorbed into the blood were analyzed using the AutodockVina 1.2.2 software.
RESULTS
Network pharmacology revealed that ZQGCD could treat LDH through a mechanism involving the chemokine signaling pathway. It was observed that the CCR2 inhibitor and ZQGCD-containing serum downregulated CCR2 and ASIC3 expression and decreased cell excitability in DRGn. The CCL2/CCR2 signaling pathway was activated in the degenerated intervertebral disc and DRG of LDH rats, increased the expression of ASIC3, and decreased the mechanical allodynia domain and thermal hyperalgesia domain. However, a CCR2 inhibitor or ZQGCD could ameliorate the above changes in LDH rats. The target proteins, CCL2 and CCR2, exhibited a robust affinity for the eight components that were absorbed into the bloodstream.
CONCLUSION
The CCL2/CCR2 pathway was activated in the intervertebral disc and DRG of LDH rats. This was accompanied by upregulation of ASIC3 expression, increased excitability of DRGn, and the occurrence of hyperalgesia. ZQGCD improves hyperalgesia in LDH rats by inhibiting the CCL2/CCR2 pathway and downregulating ASIC3 expression.
Topics: Rats; Animals; Hyperalgesia; Intervertebral Disc Displacement; Rats, Sprague-Dawley; Signal Transduction
PubMed: 37533973
DOI: 10.2147/DDDT.S415127 -
Biomolecules Dec 2021Transient receptor potential (TRP) channels are critical receptors in the transduction of nociceptive stimuli. The microenvironment of diverse types of cancer releases... (Review)
Review
Transient receptor potential (TRP) channels are critical receptors in the transduction of nociceptive stimuli. The microenvironment of diverse types of cancer releases substances, including growth factors, neurotransmitters, and inflammatory mediators, which modulate the activity of TRPs through the regulation of intracellular signaling pathways. The modulation of TRP channels is associated with the peripheral sensitization observed in patients with cancer, which results in mild noxious sensory stimuli being perceived as hyperalgesia and allodynia. Secondary metabolites derived from plant extracts can induce the activation, blocking, and desensitization of TRP channels. Thus, these compounds could act as potential therapeutic agents, as their antinociceptive properties could be beneficial in relieving cancer-derived pain. In this review, we will summarize the role of TRPV1 and TRPA1 in pain associated with cancer and discuss molecules that have been reported to modulate these channels, focusing particularly on the mechanisms of channel activation associated with molecules released in the tumor microenvironment.
Topics: Animals; Cancer Pain; Humans; Hyperalgesia; Neoplasm Proteins; Neoplasms; Signal Transduction; TRPA1 Cation Channel; TRPV Cation Channels
PubMed: 35053150
DOI: 10.3390/biom12010001