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Scientific Reports Oct 2023Nociceptive hypersensitivity is a significant side effect with the chronic administration of opioids as well as chemotherapeutics. Both opioid-induced hypersensitivity...
Nociceptive hypersensitivity is a significant side effect with the chronic administration of opioids as well as chemotherapeutics. Both opioid-induced hypersensitivity (OIH) and chemotherapy-induced hypersensitivity (CIH) are characterized by an increased sensitivity to painful stimuli which can significantly reduce the quality of life for individuals on either drug(s). Here we demonstrate the nociceptive hypersensitivity associated with repeated administration of morphine (opioid) and paclitaxel (chemotherapeutic) treatment can be reversed by oral supplementation with the short-chain fatty acid (SCFA) sodium butyrate (NaBut). In two separate mouse behavioral models for nociceptive hypersensitivity, we found that thermal hyperalgesia (for OIH) and cold allodynia (for CIH) were prevented by treatment with oral butyrate (p.o, b.i.d). Electrophysiological recordings of small diameter dorsal root ganglia (DRG) neurons from morphine and paclitaxel treated mice showed an increase in neuronal hyperexcitability in both drug models which was likewise prevented by oral butyrate treatment. Using colonic conditioned media obtained from excised colon segments we found that gut mediators of morphine treated mice can induce hyperexcitability in naïve DRG neurons, but such enhanced excitability is not present when animals are co-treated with NaBut suggesting gut derived mediators modulate neuronal hyperexcitability. In-vitro NaBut treatment did not prevent morphine-induced excitability, suggesting an indirect role of butyrate in modulating neuronal hypersensitivity. These data taken together suggest that gut derived mediators affect opioid and chemotherapeutic-induced neuronal hypersensitivity that is prevented by the SCFA butyrate.
Topics: Mice; Animals; Morphine; Analgesics, Opioid; Butyrates; Nociception; Quality of Life; Hyperalgesia; Hypersensitivity; Paclitaxel; Ganglia, Spinal
PubMed: 37853033
DOI: 10.1038/s41598-023-44857-2 -
The Journal of Headache and Pain Jun 2022Gut microbial dysbiosis and gut-brain axis dysfunction have been implicated in the pathophysiology of migraine. However, it is unclear whether migraine-related cephalic...
BACKGROUND
Gut microbial dysbiosis and gut-brain axis dysfunction have been implicated in the pathophysiology of migraine. However, it is unclear whether migraine-related cephalic allodynia could induce the alteration of gut microbial composition.
METHODS
A classic migraine rat model was established by repeated dural infusions of inflammatory soup (IS). Periorbital mechanical threshold and nociception-related behaviors were used to evaluate IS-induced cephalic allodynia and the preventive effect of topiramate. The alterations in gut microbial composition and potential metabolic pathways were investigated based on the results of 16 S rRNA gene sequencing. Microbiota-related short-chain fatty acids and tryptophan metabolites were detected and quantified by mass spectrometry analysis.
RESULTS
Repeated dural IS infusions induced cephalic allodynia (decreased mechanical threshold), migraine-like behaviors (increased immobility time and reduced moving distance), and microbial composition alteration, which were ameliorated by the treatment of topiramate. Decreased Lactobacillus was the most prominent biomarker genus in the IS-induced alteration of microbial composition. Additionally, IS infusions also enhanced metabolic pathways of the gut microbiota in butanoate, propanoate, and tryptophan, while the increased tryptophan-related metabolites indole-3-acetamide and tryptophol in feces could be the indicators.
CONCLUSIONS
Inflammatory dural stimulation-induced cephalic allodynia causes the alterations of gut microbiota profile and microbial metabolic pathways.
Topics: Animals; Gastrointestinal Microbiome; Humans; Hyperalgesia; Migraine Disorders; Rats; Rats, Sprague-Dawley; Topiramate; Tryptophan
PubMed: 35752773
DOI: 10.1186/s10194-022-01441-9 -
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 -
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 -
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 -
Muscle & Nerve Aug 2021Clinically, the chemotherapeutic agent oxaliplatin can cause peripheral neuropathy, impaired balance, and muscle wastage. Using a preclinical model, we investigated...
INTRODUCTION/AIMS
Clinically, the chemotherapeutic agent oxaliplatin can cause peripheral neuropathy, impaired balance, and muscle wastage. Using a preclinical model, we investigated whether exercise intervention could improve these adverse conditions.
METHODS
Mice were chronically treated with oxaliplatin alone or in conjunction with exercise. Behavioral studies, including mechanical allodynia, rotarod, open-field, and grip-strength tests, were performed. After euthanasia, multiple organs and four different muscle types were dissected and weighed. The cross-sectional area (CSA) of muscle fibers in the gastrocnemius muscle was assessed and gene expression analysis performed on the forelimb triceps muscle.
RESULTS
Oxaliplatin-treated mice displayed reduced weight gain, mechanical allodynia, and exploratory behavior deficits that were not significantly improved by exercise. Oxaliplatin-treated exercised mice showed modest evidence of reduced muscle wastage compared with mice treated with oxaliplatin alone, and exercised mice demonstrated evidence of a mild increase in CSA of muscle fibers.
DISCUSSION
Exercise intervention did not improve signs of peripheral neuropathy but moderately reduced the negative impact of oxaliplatin chemotherapy related to muscle morphology, suggesting the potential for exploring the impact of exercise on reducing oxaliplatin-induced neuromuscular toxicity in cancer patients.
Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Hyperalgesia; Male; Mice, Inbred C57BL; Oxaliplatin; Pain Threshold; Peripheral Nervous System Diseases; Physical Conditioning, Animal; Mice
PubMed: 34036599
DOI: 10.1002/mus.27329 -
European Journal of Pain (London,... Jan 2022The mechanism for reduced pain sensitivity associated with Alzheimer's disease (AD) has not been illustrated. We hypothesize that amyloid beta 1-42 (Aβ1-42) in the...
BACKGROUND
The mechanism for reduced pain sensitivity associated with Alzheimer's disease (AD) has not been illustrated. We hypothesize that amyloid beta 1-42 (Aβ1-42) in the spinal cord acts as an endogenous analgesic peptide to suppress pain induced by nerve injury.
METHODS
We used chronic constriction injury of the sciatic nerve (CCI) to produce neuropathic pain in Sprague-Dawley rats. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to determine the level of Aβ1-42, the expression of Wnt3a/5b and glial activation in the spinal cord. Western blotting was used to determine the expression of interleukins, the phosphorylation of NR2B and ERK1/2, and the nuclear accumulation of transcriptional factors YAP/TAZ. Thermal hyperalgesia and mechanical allodynia were assessed after CCI and pharmacological manipulations through intrathecal administration.
RESULTS
Nerve injury increases spinal level of Aβ1-42, while intrathecal administration of MK-8931 reduces the level of Aβ1-42 and facilitates mechanical allodynia. Intrathecal administration of Aβ1-42 suppresses pain behaviors in the early and late phases of neuropathy. Spinal administration of Aβ1-42 regulates the expression of interleukins, reducing glial activation and phosphorylation of NR2B and ERK1/2 in the spinal cord of CCI rats. Furthermore, intrathecal administration of Aβ1-42 decreases Wnt5b expression and suppresses the nuclear accumulation of YAP and TAZ. Blocking the interaction between Aβ1-42 and Frizzled receptors by cSP5 reverses the analgesic effects of Aβ1-42.
CONCLUSIONS
These findings suggest that spinal Aβ1-42 acts as an endogenous analgesic peptide through regulating cytokines and Wnt pathways. This study may provide a potential target for the development of novel analgesic peptides.
SIGNIFICANCE
This study provides an explanation of reduced pain sensitivity associated with Alzheimer's disease. Furthermore, our findings propose a possible physiological function of beta-amyloid1-42 to regulate pain. This study may provide a potential target for the development of novel analgesics based on an existing endogenous peptide.
Topics: Amyloid beta-Peptides; Analgesics; Animals; Hyperalgesia; Neuralgia; Rats; Rats, Sprague-Dawley; Spinal Cord
PubMed: 34288242
DOI: 10.1002/ejp.1843 -
Brain, Behavior, and Immunity Jul 2023Intrathecal delivery of interleukin-10 (IL-10) gene therapy has been reported to be effective in suppressing pain enhancement in a variety of rodent models. However, all...
Intrathecal non-viral interleukin-10 gene therapy ameliorates neuropathic pain as measured by both classical static allodynia and a novel supra-spinally mediated pain assay, the Two-Arm Rodent Somatosensory (TARS) task.
Intrathecal delivery of interleukin-10 (IL-10) gene therapy has been reported to be effective in suppressing pain enhancement in a variety of rodent models. However, all publications that have tested this treatment have relied upon measures of static allodynia (von Frey test) and thermal hyperalgesia (Hargreaves test). As this plasmid DNA IL-10 (pDNA-IL10) therapeutic approach is now in human clinical trials for multiple pain indications, including intrathecal delivery for human neuropathic pain, it is important to consider the recent concerns raised in the pain field that such tests reflect spinal rather than supraspinal processing of, and responsivity to, noxious stimuli. Consequently, this raises the question of whether intrathecal pDNA-IL10 can reverse established neuropathic pain when assessed by a test requiring supraspinal, rather than solely spinal, mediation of the behavioral response. The present study utilizes the rat sciatic chronic constriction injury (CCI) model of neuropathic pain to compare the expression of static allodynia with that of cognitively controlled choice behavior in a two-arm maze, adapted from Hayashida et al. (2019). This modification, termed the Two-Arm Rodent Somatosensory (TARS) task, provides rats free choice to reach a desired goal box via a short "arm" of the maze with tactile probes as flooring versus a longer "arm" of the maze with a smooth surface. Here we demonstrate that static allodynia and avoidance of the nociceptive flooring in TARS develop in parallel over time, and that both behaviors also resolve in parallel following intrathecal pDNA-IL10 gene therapy. Details for the construction and use of this new maze design are also provided. Together, this study documents both: (a) the important finding that intrathecal IL-10 gene therapy does indeed resolve neuropathic pain as measured by a supraspinally-mediated behavioral task, and (b) a new, supraspinally-mediated task that allows behavioral assessments across weeks and allows the analysis of both development and resolution of neuropathic pain by therapeutic interventions. As such, the TARS operant behavior task is an improvement over other approaches such as the mechanical conflict-avoidance system which have difficulties demonstrating development and reversal of pain behavior in a within-subject design.
Topics: Humans; Hyperalgesia; Interleukin-10; Neuralgia; DNA; Genetic Therapy
PubMed: 37037361
DOI: 10.1016/j.bbi.2023.04.002