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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 -
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 -
International Journal of Molecular... Jan 2018The role of neuroinflammatory cells in the establishment of neuropathic pain has been investigated in depth in the last few years. In particular, microglia have been... (Review)
Review
The role of neuroinflammatory cells in the establishment of neuropathic pain has been investigated in depth in the last few years. In particular, microglia have been shown to be key players in the induction of tactile allodynia, as they release proinflammatory molecules that, in turn, sensitize nociceptive neurons within the spinal cord. However, the role of peripheral immune cells such as macrophages, infiltrating monocytes, mast cells, and T-cells has been highlighted in the last few studies, even though the data are still conflicting and need to be clarified. Intriguingly, the central (microglia) and peripheral (T-cell)-adaptive immune cells that orchestrate maladaptive process-driven neuropathic pain seem to be involved in a gender-dependent manner. In this review, we highlight the role of the microglia and peripheral immune cells in chronic degenerative disease associated with neuro-immune-inflammatory processes.
Topics: Animals; Female; Humans; Hyperalgesia; Immune System; Male; Microglia; Neuralgia; Neuroimmunomodulation; Sex Factors; T-Lymphocyte Subsets
PubMed: 29342105
DOI: 10.3390/ijms19010281 -
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 -
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 -
European Journal of Pharmacology Mar 2017In the present work, we investigated the antinociceptive effect of gabapentin in a chronic myositis model and its interference in spinal glial cells. Chronic myositis...
In the present work, we investigated the antinociceptive effect of gabapentin in a chronic myositis model and its interference in spinal glial cells. Chronic myositis was induced by injection of Complete Freund Adjuvant (CFA) into the right gastrocnemius (GS) muscle of rats and tests for evaluating mechanical hyperalgesia, thermal hyperalgesia and tactile allodynia were performed. Pharmacological treatment with gabapentin was administrated intrathecally and 100μg and 200μg doses were tested. For analyzing astrocytes and microglia in the spinal cord, immunochemistry assay was performed. It was found that gabapentin 200μg reverted CFA-induced chronic muscle pain bilaterally, in all applied tests and it was able to attenuate microglial but not astrocytes activation in the dorsal horn of spinal cord. In conclusion, gabapentin was able to inhibit hyperalgesia and allodynia in chronic myositis and also to attenuate spinal microglial activation. Therefore, gabapentin could be used as treatment for targeting chronic muscle pain.
Topics: Amines; Animals; Astrocytes; Behavior, Animal; Cell Count; Chronic Disease; Cyclohexanecarboxylic Acids; Gabapentin; Hyperalgesia; Male; Microglia; Myalgia; Myositis; Rats; Rats, Wistar; Spinal Cord Dorsal Horn; gamma-Aminobutyric Acid
PubMed: 28192096
DOI: 10.1016/j.ejphar.2017.02.012 -
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 -
The Journal of Pain Aug 2019Learning processes have been discussed in the context of pain chronicity for decades. Particularly, operant conditioning has been used to experimentally induce and... (Meta-Analysis)
Meta-Analysis
Learning processes have been discussed in the context of pain chronicity for decades. Particularly, operant conditioning has been used to experimentally induce and modulate pain in healthy humans. In this systematic review and meta-analysis, research findings on pain facilitation (hyperalgesic effect) and pain elicitation (allodynic effect) are evaluated. The review was performed according to the PRISMA guideline and an a priori published protocol. Nine databases were searched for relevant publications: PubMed, Cochrane Register of Controlled Trials (CENTRAL), Web of Science, ScienceDirect, EBSCO, PsycINFO, MEDLINE, PsycARTICLES, and CINAHL. Studies were included if they investigated pain-free humans, exposed to an operant conditioning procedure of pain. Two independent assessors screened publications against eligibility criteria and assessed the risk of bias with the Cochrane risk of bias scale. A total of 3155 records were screened, of which 8 were included in the qualitative (401 participants) and 5 into the quantitative (110 participants) synthesis. Results showed that hyperalgesic (standardized mean difference = -0.80, 95% confidence interval = -1.33 to -0.27, P = .003) and allodynic effects (standardized mean difference = -1.27, 95% confidence interval = -2.46 to -0.08, P = .04) can be induced in healthy humans, indicating that pain can be shaped by contingencies of reinforcement. However, the uncertainty of the effect is relatively high, mostly owing to the small number of included studies, demand characteristics, and the risk of bias. This is especially relevant for studies on allodynic effects where the decrease in nociception should be more rigorously controlled. PERSPECTIVE: Operant conditioning can be a mechanism of pain chronicity. All experimental studies investigating this hypothesis have been identified and summarized. It has been demonstrated that allodynic and hyperalgesic effects can be induced by operant conditioning.
Topics: Chronic Pain; Conditioning, Operant; Humans; Hyperalgesia; Randomized Controlled Trials as Topic; Reinforcement, Psychology
PubMed: 30690165
DOI: 10.1016/j.jpain.2019.01.009 -
Neurotherapeutics : the Journal of the... Jan 2022Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting adverse effect of chemotherapy drugs such as paclitaxel (PTX). PTX causes marked molecular...
Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting adverse effect of chemotherapy drugs such as paclitaxel (PTX). PTX causes marked molecular and cellular damage, mainly in the peripheral nervous system, including sensory neurons in the dorsal root ganglia (DRG). Several studies have shown the therapeutic potential of cannabinoids, including cannabidiol (CBD), the major non-psychotomimetic compound found in the Cannabis plant, to treat peripheral neuropathies. Here, we investigated the efficacy of PECS-101 (former HUF-101), a CBD fluorinated analog, on PTX-induced neuropathic pain in mice. PECS-101, administered after the end of treatment with PTX, did not reverse mechanical allodynia. However, PECS-101 (1 mg/kg) administered along with PTX treatment caused a long-lasting relief of the mechanical and cold allodynia. These effects were blocked by a PPARγ, but not CB1 and CB2 receptor antagonists. Notably, the effects of PECS-101 on the relief of PTX-induced mechanical and cold allodynia were not found in macrophage-specific PPARγ-deficient mice. PECS-101 also decreased PTX-induced increase in Tnf, Il6, and Aif1 (Iba-1) gene expression in the DRGs and the loss of intra-epidermal nerve fibers. PECS-101 did not alter motor coordination, produce tolerance, or show abuse potential. In addition, PECS-101 did not interfere with the chemotherapeutic effects of PTX. Thus, PECS-101, a new fluorinated CBD analog, could represent a novel therapeutic alternative to prevent mechanical and cold allodynia induced by PTX potentially through the activation of PPARγ in macrophages.
Topics: Animals; Antineoplastic Agents; Cannabidiol; Disease Models, Animal; Ganglia, Spinal; Hyperalgesia; Mice; Neuralgia; PPAR gamma; Paclitaxel
PubMed: 34904193
DOI: 10.1007/s13311-021-01164-w -
Cephalalgia : An International Journal... Oct 2023To investigate whether clinical and sociodemographic factors are associated with calcitonin gene-related peptide (CGRP) induced migraine attacks.
OBJECTIVE
To investigate whether clinical and sociodemographic factors are associated with calcitonin gene-related peptide (CGRP) induced migraine attacks.
METHODS
A total of 139 participants with migraine received a 20-minute intravenous infusion of CGRP (1.5 µg/min) on a single experiment day. The incidence of CGRP-induced migraine attacks was recorded using a headache diary during the 12-hour observational period post-infusion. Univariable and multivariable regression analyses were conducted to examine potential predictors' relationship with CGRP-induced migraine attacks.
RESULTS
CGRP-induced migraine attacks were reported in 110 (79%) of 139 participants. Univariable analysis revealed that participants with cutaneous allodynia had higher odds of developing CGRP-induced migraine attacks, compared with those without allodynia (OR, 2.97, 95% CI, 1.28 to 7.43). The subsequent multivariable analysis confirmed this association (OR, 3.26, 95% CI, 1.32 to 8.69) and also found that participants with migraine with aura had lower odds of developing CGRP-induced migraine attacks (OR, 0.32, 95% CI, 0.12 to 0.84).
CONCLUSION
Our results suggest that cutaneous allodynia and aura play a role in CGRP-induced migraine attacks, while other clinical and sociodemographic factors do not seem to have any noticeable impact. This indicates that the CGRP provocation model is robust, as the CGRP hypersensitivity remained unaffected despite differences among a heterogeneous migraine population.Trial Registration: ClinicalTrials.gov Identifier: NCT04592952.
Topics: Humans; Calcitonin Gene-Related Peptide; Headache; Hyperalgesia; Migraine Disorders; Sociodemographic Factors
PubMed: 37815254
DOI: 10.1177/03331024231206375