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Cells Jun 2022Mutations in the peroxisomal half-transporter ABCD1 cause X-linked adrenoleukodystrophy, resulting in elevated very long-chain fatty acids (VLCFA), progressive...
Mutations in the peroxisomal half-transporter ABCD1 cause X-linked adrenoleukodystrophy, resulting in elevated very long-chain fatty acids (VLCFA), progressive neurodegeneration and an associated pain syndrome that is poorly understood. In the nervous system of mice, we found ABCD1 expression to be highest in dorsal root ganglia (DRG), with satellite glial cells (SGCs) displaying higher expression than neurons. We subsequently examined sensory behavior and DRG pathophysiology in mice deficient in ABCD1 compared to wild-type mice. Beginning at 8 months of age, mice developed persistent mechanical allodynia. DRG had a greater number of IB4-positive nociceptive neurons expressing PIEZO2, the mechanosensitive ion channel. Blocking PIEZO2 partially rescued the mechanical allodynia. Beyond affecting neurons, ABCD1 deficiency impacted SGCs, as demonstrated by high levels of VLCFA, increased glial fibrillary acidic protein (GFAP), as well as genes disrupting neuron-SGC connectivity. These findings suggest that lack of the peroxisomal half-transporter ABCD1 leads to PIEZO2-mediated mechanical allodynia as well as SGC dysfunction. Given the known supportive role of SGCs to neurons, this elucidates a novel mechanism underlying pain in X-linked adrenoleukodystrophy.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Adrenoleukodystrophy; Animals; Fatty Acids; Hyperalgesia; Ion Channels; Mice; Pain; Peroxisomes
PubMed: 35681537
DOI: 10.3390/cells11111842 -
International Journal of Molecular... Aug 2019Recent research in the last decade has sought to explore the role and therapeutic potential of Liver X Receptors (LXRs) in the physiology and pathologies of the... (Review)
Review
Recent research in the last decade has sought to explore the role and therapeutic potential of Liver X Receptors (LXRs) in the physiology and pathologies of the Peripheral Nervous System. LXRs have been shown to be important in maintaining the redox homeostasis in peripheral nerves for proper myelination, and they regulate ER stress in sensory neurons. Furthermore, LXR stimulation has a positive impact on abrogating the effects of diabetic peripheral neuropathy and obesity-induced allodynia in the Peripheral Nervous System (PNS). This review details these findings and addresses certain important questions that are yet to be answered. The potential roles of LXRs in different cells of the PNS are speculated based on existing knowledge. The review also aims to provide important perspectives for further research in elucidating the role of LXRs and assessing the potential of LXR based therapies to combat pathologies of the Peripheral Nervous System.
Topics: Ganglia, Sensory; Humans; Hyperalgesia; Liver X Receptors; Obesity; Oxysterols; Schwann Cells
PubMed: 31461876
DOI: 10.3390/ijms20174192 -
International Journal of Molecular... Jun 2023Phosphorylation of the serine 139 of the histone variant H2AX (γH2AX) is a DNA damage marker that regulates DNA damage response and various diseases. However, whether...
Phosphorylation of the serine 139 of the histone variant H2AX (γH2AX) is a DNA damage marker that regulates DNA damage response and various diseases. However, whether γH2AX is involved in neuropathic pain is still unclear. We found the expression of γH2AX and H2AX decreased in mice dorsal root ganglion (DRG) after spared nerve injury (SNI). Ataxia telangiectasia mutated (ATM), which promotes γH2AX, was also down-regulated in DRG after peripheral nerve injury. ATM inhibitor KU55933 decreased the level of γH2AX in ND7/23 cells. The intrathecal injection of KU55933 down-regulated DRG γH2AX expression and significantly induced mechanical allodynia and thermal hyperalgesia in a dose-dependent manner. The inhibition of ATM by siRNA could also decrease the pain threshold. The inhibition of dephosphorylation of γH2AX by protein phosphatase 2A (PP2A) siRNA partially suppressed the down-regulation of γH2AX after SNI and relieved pain behavior. Further exploration of the mechanism revealed that inhibiting ATM by KU55933 up-regulated extracellular-signal regulated kinase (ERK) phosphorylation and down-regulated potassium ion channel genes, such as potassium voltage-gated channel subfamily Q member 2 () and potassium voltage-gated channel subfamily D member 2 () in vivo, and KU559333 enhanced sensory neuron excitability in vitro. These preliminary findings imply that the down-regulation of γH2AX may contribute to neuropathic pain.
Topics: Animals; Mice; Ganglia, Spinal; Hyperalgesia; Neuralgia; Peripheral Nerve Injuries; Potassium; RNA, Small Interfering; Sensory Receptor Cells; Shal Potassium Channels
PubMed: 37373296
DOI: 10.3390/ijms241210148 -
Scientific Reports Jan 2021Cutaneous allodynia (CA) is a pain in response to non-nociceptive stimulation and a marker of central sensitisation. Probable migraine (PM) is a migraine subtype that... (Clinical Trial)
Clinical Trial
Cutaneous allodynia (CA) is a pain in response to non-nociceptive stimulation and a marker of central sensitisation. Probable migraine (PM) is a migraine subtype that fulfils all but one criterion of migraine. Headache intensity and the disability of individuals with PM are similar or lower than individuals with migraine. This study compared CA prevalence and characteristics of PM and migraine using a nationally representative sample in Korea. The Allodynia Symptom Checklist-12 (ASC-12) was used to assess CA (ASC-12 score ≥ 3). PM and migraine prevalence were 11.6% and 5.0%, respectively. CA prevalence did not significantly differ between PM and migraine (14.5% vs. 16.0%, p = 0.701). Participants with PM with CA reported a higher monthly headache frequency (3.3 ± 4.3 vs. 1.8 ± 3.6, p = 0.044), more severe headache intensity (Visuals Analogue Scale, 6.0 [4.0-7.0] vs. 5.0 [3.0-6.0], p = 0.002), and higher impact of headache (Headache Impact Test-6, 56.3 ± 7.2 vs. 48.3 ± 8.0, p < 0.001) than those without CA. Multiple regression analyses revealed that headache frequency and intensity, anxiety, and depression were significant factors for CA in participants with PM. In conclusion, CA prevalence among participants with PM and migraine were comparable. Anxiety, depression, and headache frequency and intensity were significant factors for CA in participants with PM.
Topics: Adult; Aged; Female; Humans; Hyperalgesia; Male; Middle Aged; Migraine Disorders; Prevalence; Republic of Korea
PubMed: 33510340
DOI: 10.1038/s41598-021-82080-z -
Molecular Pain 2021Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes severe neuropathic pain typically encompassing cold allodynia and long-lasting mechanical...
Endothelin receptor type A is involved in the development of oxaliplatin-induced mechanical allodynia and cold allodynia acting through spinal and peripheral mechanisms in rats.
Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes severe neuropathic pain typically encompassing cold allodynia and long-lasting mechanical allodynia. Endothelin has been shown to modulate nociceptive transmission in a variety of pain disorders. However, the action of endothelin varies greatly depending on many variables, including pain causes, receptor types (endothelin type A (ET) and B (ET) receptors) and organs (periphery and spinal cord). Therefore, in this study, we investigated the role of endothelin in a Sprague-Dawley rat model of oxaliplatin-induced neuropathic pain. Intraperitoneal administration of bosentan, a dual ET/ET receptor antagonist, effectively blocked the development or prevented the onset of both cold allodynia and mechanical allodynia. The preventive effects were exclusively mediated by ET receptor antagonism. Intrathecal administration of an ET receptor antagonist prevented development of long-lasting mechanical allodynia but not cold allodynia. In marked contrast, an intraplantar ET receptor antagonist had a suppressive effect on cold allodynia but only had a partial and transient effect on mechanical allodynia. In conclusion, ET receptor antagonism effectively prevented long-lasting mechanical allodynia through spinal and peripheral actions, while cold allodynia was prevented through peripheral actions.
Topics: Animals; Hyperalgesia; Neuralgia; Oxaliplatin; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A
PubMed: 34894846
DOI: 10.1177/17448069211058004 -
BMC Anesthesiology Jul 2022Persistent postoperative pain causes influence the life quality of many patients. The Epac/PKC pathway has been indicated to regulate mechanical hyperalgesia. The...
Persistent postoperative pain causes influence the life quality of many patients. The Epac/PKC pathway has been indicated to regulate mechanical hyperalgesia. The present study used skin/muscle incision and retraction (SMIR) to induce postoperative pain in rats and evaluated the Epac/PKC pathway in postoperative pain. Mechanical allodynia was assessed by paw withdrawal threshold before and after incision. The levels of Epac, PKC, proinflammatory cytokines, and blood-nerve barrier-related proteins were assessed using Western blotting. We found that SMIR induced the activation of the Epac/PKC pathway, mechanical allodynia, and upregulation of Glut1, VEGF, and PGP9.5 proteins in dorsal root ganglia. Under the influence of agonists of Epac/PKC, normal rats showed mechanical allodynia and increased Glut1, VEGF, and PGP9.5 proteins. After inhibition of Epac1 in rats with SMIR, mechanical allodynia was alleviated, and proinflammatory cytokines and Glut1, VEGF, and PGP9.5 proteins were decreased. Moreover, dorsal root ganglia neurons showed abnormal proliferation under the activation of the Epac/PKC pathway. Using Captopril to protect vascular endothelial cells after SMIR had a positive effect on postoperative pain. In conclusion, SMIR regulates the persistent postoperative pain in rats by the Epac/PKC pathway.
Topics: Animals; Cytokines; Endothelial Cells; Ganglia, Spinal; Glucose Transporter Type 1; Guanine Nucleotide Exchange Factors; Hyperalgesia; Muscles; Pain, Postoperative; Protein Kinase C beta; Rats; Rats, Sprague-Dawley; Skin; Vascular Endothelial Growth Factor A
PubMed: 35850627
DOI: 10.1186/s12871-022-01771-w -
BMC Complementary Medicine and Therapies Jun 2024Gastrodin (GAS), a main bioactive component of the herbal plant, Gastrodia elata Blume, has shown to have beneficial effects on neuroinflammatory diseases such as...
BACKGROUND
Gastrodin (GAS), a main bioactive component of the herbal plant, Gastrodia elata Blume, has shown to have beneficial effects on neuroinflammatory diseases such as Alzheimer's disease in animal studies and migraine in clinical studies. Inflammasome is a multimeric protein complex having a core of pattern recognition receptor and has been implicated in the development of neuroinflammatory diseases. Gastrodin has shown to modulate the activation of nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. This study investigated the effects of GAS on the intensity of mechanical allodynia and associated changes in NLRP3 inflammasome expression at the spinal level using L5/6 spinal nerve ligation model (SNL) in rats.
METHODS
Intrathecal (IT) catheter implantation and SNL were used for drug administration and pain model in male Sprague-Dawley rats. The effect of gastrodin or MCC950 (NLRP3 inflammasome inhibitor) on mechanical allodynia was measured by von Frey test. Changes in NLRP3 inflammasome components and interleukin-1β (IL-1β) and cellular expression were examined in the spinal cord and dorsal root ganglion.
RESULTS
The expression of NLRP3 inflammasome components was found mostly in the neurons in the spinal cord and dorsal root ganglion. The protein and mRNA levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and IL-1β were upregulated in SNL animals compared to Sham animals. IT administration of GAS significantly attenuated the expression of NLRP3 inflammasome and the intensity of SNL-induced mechanical allodynia. NLRP3 inflammasome inhibitor, MCC950, also attenuated the intensity of allodynia, but the effect is less strong and shorter than that of GAS.
CONCLUSIONS
Expression of NLRP3 inflammasome and IL-1β is greatly increased and mostly found in the neurons at the spinal level in SNL model, and IT gastrodin exerts a significant anti-allodynic effect in SNL model partly through suppressing the expression of NLRP3 inflammasome.
Topics: Animals; NLR Family, Pyrin Domain-Containing 3 Protein; Benzyl Alcohols; Glucosides; Rats, Sprague-Dawley; Male; Rats; Disease Models, Animal; Inflammasomes; Hyperalgesia; Spinal Nerves; Injections, Spinal
PubMed: 38835032
DOI: 10.1186/s12906-024-04519-w -
Pain Physician May 2023Clinically, neuropathic pain is a severe side effect of oxaliplatin chemotherapy, which usually leads to dose reduction or cessation of treatment. Due to the unawareness...
BACKGROUND
Clinically, neuropathic pain is a severe side effect of oxaliplatin chemotherapy, which usually leads to dose reduction or cessation of treatment. Due to the unawareness of detailed mechanisms of oxaliplatin-induced neuropathic pain, it is difficult to develop an effective therapy and limits its clinical use.
OBJECTIVES
The aim of the present study was to identify the role of sirtuin 1 (SIRT1) reduction in epigenetic regulation of the expression of voltage-gated sodium channels 1.7 (Nav1.7) in the dorsal root ganglion (DRG) during oxaliplatin-induced neuropathic pain.
STUDY DESIGN
Controlled animal study.
SETTING
University laboratory.
METHODS
The von Frey test was performed to evaluate pain behavior in rats. Real-time quantitative polymerase chain reaction, western blotting, electrophysiological recording, chromatin immunoprecipitation, and small interfering RNA (siRNA) were used to illustrate the mechanisms.
RESULTS
In the present study, we found that both the activity and expression of SIRT1 were significantly decreased in rat DRG following oxaliplatin treatment. The activator of SIRT1, resveratrol, not only increased the activity and expression of SIRT1, but also attenuated the mechanical allodynia following oxaliplatin treatment. In addition, local knockdown of SIRT1 by intrathecal injection of SIRT1 siRNA caused mechanical allodynia in naive rats. Besides, oxaliplatin treatment enhanced the action potential firing frequency of DRG neurons and the expression of Nav1.7 in DRG and activation of SIRT1 by resveratrol reversed this effect. Furthermore, blocking Nav1.7 by ProTx II (a selective Nav1.7 channel blocker) reversed oxaliplatin-induced mechanical allodynia. In addition, histone H3 hyperacetylation at the Nav1.7 promoter in DRG of rats following oxaliplatin treatment was significantly suppressed by activation of SIRT1 with resveratrol. Moreover, both the expression of Nav1.7 and histone H3 acetylation at the Nav1.7 promoter were upregulated in the DRG by local knockdown of SIRT1 with SIRT1 siRNA in naive rats.
LIMITATIONS
More underlying mechanism(s) of SIRT1 reduction after oxaliplatin treatment needs to be explored in future research.
CONCLUSIONS
These findings suggest that reduction of SIRT1-mediated epigenetic upregulation of Nav1.7 in the DRG contributes to the development of oxaliplatin-induced neuropathic pain in rats. The intrathecal drug delivery treatment of activating SIRT1 might be a novel therapeutic option for oxaliplatin-induced neuropathic pain.
Topics: Rats; Animals; Oxaliplatin; Up-Regulation; Sirtuin 1; Hyperalgesia; Rats, Sprague-Dawley; Histones; Epigenesis, Genetic; Resveratrol; Neuralgia; Ganglia, Spinal; RNA, Small Interfering
PubMed: 37192244
DOI: No ID Found -
Scientific Reports Oct 2023Deficiency of an extracellular matrix glycoprotein tenascin-X (TNX) leads to a human heritable disorder Ehlers-Danlos syndrome, and TNX-deficient patients complain of...
Deficiency of an extracellular matrix glycoprotein tenascin-X (TNX) leads to a human heritable disorder Ehlers-Danlos syndrome, and TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. We previously reported that TNX-deficient (Tnxb) mice exhibit mechanical allodynia and hypersensitivity to myelinated A-fibers. Here, we investigated the pain response of Tnxb mice using pharmacological silencing of A-fibers with co-injection of N-(2,6-Dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314), a membrane-impermeable lidocaine analog, plus flagellin, a toll-like receptor 5 (TLR5) ligand. Intraplantar co-injection of QX-314 and flagellin significantly increased the paw withdrawal threshold to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aβ fiber responses), but not 5 Hz (C fiber responses) in wild-type mice. The QX-314 plus flagellin-induced silencing of Aδ- and Aβ-fibers was also observed in Tnxb mice. Co-injection of QX-314 and flagellin significantly inhibited the mechanical allodynia and neuronal activation of the spinal dorsal horn in Tnxb mice. Interestingly, QX-314 alone inhibited the mechanical allodynia in Tnxb mice, and it increased the paw withdrawal threshold to stimuli at frequencies of 250 Hz and 2000 Hz in Tnxb mice, but not in wild-type mice. The inhibition of mechanical allodynia induced by QX-314 alone was blocked by intraplantar injection of a TLR5 antagonist TH1020 in Tnxb mice. These results suggest that mechanical allodynia due to TNX deficiency is caused by the hypersensitivity of Aδ- and Aβ-fibers, and it is induced by constitutive activation of TLR5.
Topics: Animals; Humans; Mice; Ehlers-Danlos Syndrome; Extracellular Matrix; Flagellin; Hyperalgesia; Nerve Fibers, Unmyelinated; Tenascin; Toll-Like Receptor 5
PubMed: 37898719
DOI: 10.1038/s41598-023-45638-7 -
Health Psychology : Official Journal of... Oct 2020Pain catastrophizing and cutaneous allodynia represent two risk factors for greater headache-related disability. Yet, there is limited knowledge of the extent to which... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Pain catastrophizing and cutaneous allodynia represent two risk factors for greater headache-related disability. Yet, there is limited knowledge of the extent to which these risk factors are modifiable and whether nonpharmacological treatment-related changes are associated with migraine improvements. Using data from the Women's Health and Migraine (WHAM) study, a randomized controlled trial that compared effects of behavioral weight loss (BWL) and migraine education (ME) in women with migraine and overweight/obesity, we tested whether: (a) BWL versus ME produced greater changes in pain catastrophizing and allodynia from baseline across posttreatment and follow-up time points, and (b) whether these improvements were associated with improvements in headache disability.
METHOD
Women ( = 110) were randomly assigned to 16 weeks of either BWL or ME and assessed at baseline, posttreatment, and follow up (32 weeks). Multilevel mixed effects modeling tested: (a) for between-groups differences in pain catastrophizing and allodynia changes over time, and (b) associations of changes in pain catastrophizing and allodynia with changes in headache disability, adjusting for migraine severity and weight loss.
RESULTS
Both BWL and ME had significant reductions in pain catastrophizing and allodynia from baseline to posttreatment and follow up, and the improvements were comparable across conditions. Reductions in pain catastrophizing and cutaneous allodynia were associated with significant reductions in headache disability, even when controlling for intervention-related improvements in migraine and weight loss.
CONCLUSION
Pain catastrophizing and allodynia are not only reduced after nonpharmacologic treatments for migraine, but greater improvements are associated with greater reductions in headache-related disability, independent of migraine severity. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Topics: Adolescent; Adult; Female; Humans; Hyperalgesia; Middle Aged; Migraine Disorders; Obesity; Overweight; Pain; Young Adult
PubMed: 32658497
DOI: 10.1037/hea0000920