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1.
J Neuroinflammation ; 19(1): 80, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35387668

RESUMO

BACKGROUND: Neuroinflammation in spinal dorsal horn (SDH) plays an important role in the pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS). Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) exert potent anti-inflammatory activities in the treatment of various diseases. This study aimed to determine the therapeutic effects of MSC-EVs on IC and furtherly investigate the potential mechanism to attenuate neuroinflammation. METHODS: Female IC rat model was established by intraperitoneal injection of cyclophosphamide (50 mg/kg, every 3 days for 3 doses). Inhibition of NLRP3 inflammasome was performed by intraperitoneal injection of MCC950 (10 mg/kg). MSC-EVs were isolated from the culture supernatants of human umbilical cord derived MSCs using ultracentrifugation, and then injected intrathecally into IC rats (20 µg in 10 µl PBS, every other day for 3 doses). Suprapubic mechanical allodynia was assessed using up-down method with von Frey filaments, and micturition frequency was examined by urodynamics. The expression of NLRP3 inflammasome components (NLRP3 and Caspase-1), glial cell markers (IBA-1 and GFAP), proinflammatory cytokines (TNF-α, IL-1ß, IL-6 and IL-18) and TLR4/NF-κB signal pathway (TLR4, p65 NK-κB and phospho-p65 NK-κB) in L6-S1 SDH was measured by Western blot analysis. The cellular localization of NLRP3 in SDH was detected using immunofluorescence co-staining. RESULTS: NLRP3 inflammasome was activated in neurons in SDH of IC rats. NLRP3 inflammasome activation contributed to activation of glial cells and process of spinal neuroinflammation in IC rats, and was related to suprapubic mechanical allodynia and frequent micturition. Intrathecal injection of MSC-EVs alleviated suprapubic mechanical allodynia and frequent micturition in IC rats, restrained activation of glial cells and attenuated neuroinflammation in SDH. In addition, MSC-EV treatment significantly inhibited activation of both NLRP3 inflammasomes and TLR4/NF-κB signal pathway. CONCLUSIONS: NLRP3 inflammasome activation is involved in the neuroinflammation of IC. Intrathecal injection of MSC-EVs alleviates neuroinflammation and mechanical allodynia in IC by inhibiting the activation of NLRP3 inflammasome, and TLR4/NF-κB signal pathway may be the potential regulatory target.


Assuntos
Cistite Intersticial , Vesículas Extracelulares , Células-Tronco Mesenquimais , Animais , Cistite Intersticial/complicações , Vesículas Extracelulares/metabolismo , Feminino , Hiperalgesia/etiologia , Inflamassomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo
2.
Physiol Behav ; 251: 113807, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35427673

RESUMO

BACKGROUND: Cell therapy is a promising treatment method for relieving neuropathic pain caused by spinal cord injuries (SCI). Sertoli cells (SCs) are an attractive choice given their demonstrated secretion of growth factors and immunosuppressant effect. This study mechanistically characterizes the analgesic effect of SCs transplantation. METHODS: The clip compression SCI model was carried out on the T12-T13 level in male Wistar rats. One-week post-SCI, SCs were transplanted into the site of injury. Animals underwent Basso, Beattie, and Bresnahan locomotor scoring, mechanical allodynia, and thermal hyperalgesia on a weekly basis for a duration of six weeks. Histological examination of the spinal cord and molecular evaluation of Iba-1, P2Y4, TRPC6, and P-mTOR were performed. SCs survival, measured by anti-Müllerian hormone expression in the spinal cord. RESULTS: Animals that received SCs transplantation showed improvement in motor function recovery and pain relief. Furthermore, a cavity was significantly decreased in the transplanted animals (p = 0.0024), the expression level of TRPC6 and caspase3 and the number of activated microglia decreased compared to the SCI animals, and p-mTOR and P2Y4R expression remarkably increased compared to the SCI group. CONCLUSION: SCs transplantation produces an analgesic effect which may represent a promising treatment for SCI-induced chronic pain.


Assuntos
Neuralgia , Traumatismos da Medula Espinal , Analgésicos , Animais , Transplante de Células/efeitos adversos , Hiperalgesia/etiologia , Hiperalgesia/terapia , Masculino , Microglia/metabolismo , Neuralgia/etiologia , Neuralgia/metabolismo , Neuralgia/terapia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Células de Sertoli/metabolismo , Células de Sertoli/patologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/terapia , Serina-Treonina Quinases TOR/metabolismo , Canais de Cátion TRPC , Canal de Cátion TRPC6/metabolismo
3.
Int J Mol Sci ; 23(8)2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35456908

RESUMO

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 ß-catenin. Moreover, resveratrol reduced the levels of TNF-α and IL-18 that are target genes strictly downstream of the WNT/ß-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/ß-catenin pathway and the related inflammatory and oxidative alterations, thus alleviating the behavioral changes induced by LBP.


Assuntos
Dor Lombar , beta Catenina , Animais , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Inflamação/tratamento farmacológico , Dor Lombar/tratamento farmacológico , Dor Lombar/etiologia , Ratos , Ratos Sprague-Dawley , Resveratrol/uso terapêutico , Via de Sinalização Wnt , beta Catenina/metabolismo
4.
Neurosci Bull ; 38(4): 386-402, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35471719

RESUMO

Myocardial ischemia (MI) causes somatic referred pain and sympathetic hyperactivity, and the role of sensory inputs from referred areas in cardiac function and sympathetic hyperactivity remain unclear. Here, in a rat model, we showed that MI not only led to referred mechanical hypersensitivity on the forelimbs and upper back, but also elicited sympathetic sprouting in the skin of the referred area and C8-T6 dorsal root ganglia, and increased cardiac sympathetic tone, indicating sympathetic-sensory coupling. Moreover, intensifying referred hyperalgesic inputs with noxious mechanical, thermal, and electro-stimulation (ES) of the forearm augmented sympathetic hyperactivity and regulated cardiac function, whereas deafferentation of the left brachial plexus diminished sympathoexcitation. Intradermal injection of the α2 adrenoceptor (α2AR) antagonist yohimbine and agonist dexmedetomidine in the forearm attenuated the cardiac adjustment by ES. Overall, these findings suggest that sensory inputs from the referred pain area contribute to cardiac functional adjustment via peripheral α2AR-mediated sympathetic-sensory coupling.


Assuntos
Hiperalgesia , Isquemia Miocárdica , Animais , Gânglios Espinais , Hiperalgesia/etiologia , Isquemia Miocárdica/complicações , Dor Referida/complicações , Ratos , Sistema Nervoso Simpático
5.
Behav Brain Res ; 425: 113829, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35248649

RESUMO

Post-traumatic trigeminal neuropathy (PTTN) is a chronic sensory disorder that afflicts patients with nerve injury caused by orofacial and dental surgery or cervicofacial trauma. Currently, effective treatment strategies for PTTN are lacking, and patients treated with conventional drugs for PTTN experience adverse effects such as drowsiness and drug addiction. In the present study, we investigated whether mirogabalin, a novel gabapentinoid, could be an effective treatment for PTTN induced by distal infraorbital nerve chronic constriction injury (dIoN-CCI) in the mouse. Increased facial grooming time and hyper-responsiveness to acetone were observed in dIoN-CCI mice. These pain-related behaviors were attenuated by intraperitoneal injection of mirogabalin. In particular, mirogabalin significantly diminished the increase in facial grooming time. The analgesic effect of mirogabalin injection started 45 min after the injection and persisted for 6 h. Additionally, 10 mg/kg mirogabalin did not affect locomotor activity in the open field test, suggesting that it does not cause sedation. Together, the current findings suggest that mirogabalin could be a valuable therapeutic drug for PTTN following orofacial surgeries without sedative side effects.


Assuntos
Nociceptividade , Traumatismos do Nervo Trigêmeo , Animais , Compostos Bicíclicos com Pontes/farmacologia , Modelos Animais de Doenças , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Camundongos , Traumatismos do Nervo Trigêmeo/complicações , Traumatismos do Nervo Trigêmeo/tratamento farmacológico
6.
Eur J Pain ; 26(5): 1107-1122, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35263811

RESUMO

BACKGROUND: Central neuropathic pain (CNP) is an excruciating condition, prevalent in up to a third of patients with multiple sclerosis (MS). Identifying CNP among MS patients is particularly challenging considering the ample comorbid chronic pain conditions and sensory disturbances entailed by the disease. The aim was to identify sensory features unique to CNP beyond those of chronic pain and MS. METHODS: Participants were 112 MS patients: 44 with a diagnosis of CNP, 28 with a diagnosis of chronic musculoskeletal pain (MSP), and 40 pain free. Participants underwent testing of thermal and mechanical thresholds, thermal grill illusion (TGI), pain adaptation (PA), and offset analgesia (OA), and chronic pain was characterized. A two-step cluster analysis was performed, and the association between the cluster membership and the clinical group membership (CNP, MSP, pain free) was evaluated. RESULTS: The CNP and MSP groups were similar in most of the chronic pain variables (e.g., severity, location and quality) and MS-related variables (e.g., type, severity and medication intake). The three created clusters had unique sensory features: (1) 'Hyposensitivity' (increased thermal and touch thresholds) characterized the CNP group; (2) 'Poor inhibition and hyperalgesia' (worst PA and OA and decreased TGI threshold) characterized the MSP group; and (3) 'Efficient inhibition' (best PA and OA, smallest sensory loss) characterized the pain-free group. CONCLUSIONS: The unique sensory features of CNP and MSP provide insight into their pathophysiology, and evaluating them may increase the ability to provide individually based interventions. Efficient inhibition may protect MS patients from chronic pain. SIGNIFICANCE: Cluster analysis among patients with multiple sclerosis (MS) revealed that while central neuropathic pain is associated with thermal and mechanical hypoesthesia, musculoskeletal pain is involved with reduced pain inhibition and hyperalgesia; sensory profiles that provide insights into the mechanisms of these conditions and may promote an individually based pain management.


Assuntos
Dor Crônica , Ilusões , Esclerose Múltipla , Dor Musculoesquelética , Neuralgia , Análise por Conglomerados , Humanos , Hiperalgesia/etiologia , Esclerose Múltipla/complicações , Neuralgia/etiologia , Medição da Dor , Limiar da Dor/fisiologia
7.
Exp Neurol ; 352: 114048, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35304102

RESUMO

Spinal cord injury (SCI) frequently results in immediate and sustained neurological dysfunction, including intractable neuropathic pain in approximately 60-80% of individuals. SCI induces immediate mechanical damage to spinal cord tissue followed by a period of secondary injury in which tissue damage is further propagated, contributing to the development of anatomically unique lesions. Variability in lesion size and location influences the degree of motor and sensory dysfunction incurred by an individual. We predicted that variability in lesion parameters may also explain why some, but not all, experimental animals develop mechanical sensitivity after SCI. To characterize the relationship of lesion anatomy to mechanical allodynia, we utilized a mouse cervical hemicontusion model of SCI that has been shown to lead to the development and persistence of mechanical allodynia in the ipsilateral forelimb after injury. At four weeks post-SCI, the numbers and locations of surviving neurons were quantified along with total lesion volume and nociceptive fiber sprouting. We found that the subset of animals exhibiting mechanical allodynia had significantly increased neuronal sparing in the ipsilateral dorsal horn around the lesion epicenter compared to animals that did not exhibit mechanical allodynia. Additionally, we failed to observe significant differences between groups in nociceptive fiber density in the dorsal horn around the lesion epicenter. Notably, we found that impactor probe displacement upon administration of the SCI surgery was significantly lower in sensitive animals compared with not-sensitive animals. Together, our data indicate that lesion severity negatively correlates with the manifestation of at-level mechanical hypersensitivity and suggests that sparing of dorsal horn neurons may be required for the development of neuropathic pain.


Assuntos
Medula Cervical , Neuralgia , Traumatismos da Medula Espinal , Animais , Modelos Animais de Doenças , Hiperalgesia/etiologia , Hiperalgesia/patologia , Camundongos , Neuralgia/patologia , Células do Corno Posterior/patologia , Medula Espinal/patologia , Corno Dorsal da Medula Espinal/patologia
8.
Comput Math Methods Med ; 2022: 1080858, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35309843

RESUMO

Objective: To explore the changes of entropy index and cerebral oxygen metabolism in the maintenance of remifentanil anesthesia and the predictive value of postoperative hyperalgesia. Methods: A total of 266 patients undergoing general anesthesia in our hospital from January 2020 to October 2021 were selected, and remifentanil was used to maintain anesthesia. The state entropy, reaction entropy, and cerebral oxygen metabolism indexes (cerebral oxygen uptake rate (CERO2), arterial-venous blood oxygen difference (Da-jvO2)) of patients before induction of anesthesia, 15 minutes during the operation, and at the end of the operation were compared. The influencing factors of postoperative hyperalgesia were analyzed. The logistic regression model of postoperative hyperalgesia was established, and the value of entropy index and cerebral oxygen metabolism in predicting postoperative hyperalgesia was evaluated by drawing the receiver operating characteristic curve (ROC). Results: The state entropy, response entropy, and CERO2 at 30 min during the operation and at the end of the operation were lower than those before the induction of anesthesia, and Da-jvO2 was higher than that before the induction of anesthesia (P < 0.001). At the end of the operation, the state entropy, reaction entropy, and CERO2 were higher than 30 minutes during the operation, and Da-jvO2 was lower than 30 minutes during the operation (P < 0.001). The dosage of remifentanil, reaction entropy, and CERO2 at the end of the operation entered the logistic model. The AUC value of the reaction entropy and CERO2 combined to predict postoperative hyperalgesia at the end of the operation was 0.851 greater than the reaction entropy at the end of the operation (χ 2 = 3.847, P = 0.036), CERO2 (χ 2 = 2.589, P = 0.010) single index predictive value. Conclusion: The entropy index and cerebral oxygen metabolism in general anesthesia patients change with the progress and discontinuation of remifentanil maintenance anesthesia, and the combination of the two has a high predictive power in postoperative hyperalgesia risk assessment. When the reaction entropy > 54.23, CERO2 > 34.14%, or the total dosage of remifentanil ≥ 30 µg/kg at the end of the operation, we should be highly vigilant of the occurrence of postoperative hyperalgesia and postoperative analgesia management should be strengthened.


Assuntos
Analgésicos Opioides/administração & dosagem , Encéfalo/metabolismo , Hiperalgesia/etiologia , Dor Pós-Operatória/etiologia , Remifentanil/administração & dosagem , Adolescente , Adulto , Analgésicos Opioides/efeitos adversos , Anestesia Geral/efeitos adversos , Anestesia Geral/métodos , Encéfalo/efeitos dos fármacos , Biologia Computacional , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Remifentanil/efeitos adversos , Adulto Jovem
9.
J Neuroinflammation ; 19(1): 57, 2022 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-35219337

RESUMO

BACKGROUND: Peripheral neuropathy is a common and progressive disorder in the elderly that interferes with daily activities. It is of importance to find efficient treatments to treat or delay this age-related neurodegeneration. Silencing macrophages by reducing foamy macrophages showed significant improvement of age-related degenerative changes in peripheral nerves of aged mice. We previously demonstrated that activation of the cholesterol sensor Liver X receptor (LXR) with the potent agonist, GW3965, alleviates pain in a diet-induced obesity model. We sought to test whether LXR activation may improve neuropathy in aged mice. METHODS: 21-month-old mice were treated with GW3965 (25 mg/Kg body weight) for 3 months while testing for mechanical allodynia and thermal hyperalgesia. At termination, flow cytometry was used to profile dorsal root ganglia and sciatic nerve cells. Immune cells were sorted and analyzed for cholesterol and gene expression. Nerve fibers of the skin from the paws were analyzed. Some human sural nerves were also evaluated. Comparisons were made using either t test or one-way ANOVA. RESULTS: Treatment with GW3965 prevented the development of mechanical hypersensitivity and thermal hyperalgesia over time in aged mice. We also observed change in polarization and cholesterol content of sciatic nerve macrophages accompanied by a significant increase in nerve fibers of the skin. CONCLUSIONS: These results suggest that activation of the LXR may delay the PNS aging by modifying nerve-immune cell lipid content. Our study provides new potential targets to treat or delay neuropathy during aging.


Assuntos
Doenças do Sistema Nervoso Periférico , Animais , Gânglios Espinais/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Receptores X do Fígado/agonistas , Camundongos , Doenças do Sistema Nervoso Periférico/metabolismo , Nervo Isquiático/metabolismo
10.
Glia ; 70(4): 675-696, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35050555

RESUMO

Neuropathic pain is a prevalent and debilitating chronic disease that is characterized by activation in glial cells in various pain-related regions within the central nervous system. Recent studies have suggested a sexually dimorphic role of microglia in the maintenance of neuropathic pain in rodents. Here, we utilized RNA sequencing analysis and in vitro primary cultures of microglia to identify whether there is a common neuropathic microglial signature and characterize the sex differences in microglia in pain-related regions in nerve injury and chemotherapy-induced peripheral neuropathy mouse models. While mechanical allodynia and behavioral changes were observed in all models, transcriptomic analysis of microglia revealed no common transcriptional changes in spinal and supraspinal regions and in the different neuropathic models. However, there was a substantial change in microglial gene expression within the ipsilateral lumbar spinal cord 7 days after chronic constriction injury (CCI) of the sciatic nerve. Both sexes upregulated genes associated with inflammation, phagosome, and lysosome activation, though males revealed a prominent global transcriptional shift not observed in female mice. Transcriptomic comparison between male spinal microglia after CCI and data from other nerve injury models and neurodegenerative microglia demonstrated a unique CCI-induced signature reflecting acute activation of microglia. Further, in vitro studies revealed that only male microglia from nerve-injured mice developed a reactive phenotype with increased phagocytotic activity. This study demonstrates a lack of a common neuropathic microglial signature and indicates distinct sex differences in spinal microglia, suggesting they contribute to the sex-specific pain processing following nerve injury.


Assuntos
Neuralgia , Traumatismos dos Nervos Periféricos , Animais , Feminino , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Masculino , Camundongos , Microglia/metabolismo , Neuralgia/metabolismo , Traumatismos dos Nervos Periféricos/complicações , Traumatismos dos Nervos Periféricos/metabolismo , Nervo Isquiático/metabolismo , Medula Espinal/metabolismo , Transcriptoma
11.
Int J Mol Sci ; 23(2)2022 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-35055141

RESUMO

Chronic pain is associated with time-dependent structural and functional reorganization of the prefrontal cortex that may reflect adaptive pain compensatory and/or maladaptive pain-promoting mechanisms. However, the molecular underpinnings of these changes and whether there are time-dependent relationships to pain progression are not well characterized. In this study, we analyzed protein composition in the medial prefrontal cortex (mPFC) of rats at two timepoints after spinal nerve ligation (SNL) using two-dimensional gel electrophoresis (2D-ELFO) and liquid chromatography with tandem mass spectrometry (LC-MS/MS). SNL, but not sham-operated, rats developed persistent tactile allodynia and thermal hyperalgesia, confirming the presence of experimental neuropathic pain. Two weeks after SNL (early timepoint), we identified 11 proteins involved in signal transduction, protein transport, cell homeostasis, metabolism, and apoptosis, as well as heat-shock proteins and chaperones that were upregulated by more than 1.5-fold compared to the sham-operated rats. Interestingly, there were only four significantly altered proteins identified at 8 weeks after SNL (late timepoint). These findings demonstrate extensive time-dependent modifications of protein expression in the rat mPFC under a chronic neuropathic pain state that might underlie the evolution of chronic pain characterized by early pain-compensatory and later aberrant mechanisms.


Assuntos
Hiperalgesia/metabolismo , Neuralgia/metabolismo , Córtex Pré-Frontal/metabolismo , Proteômica/métodos , Nervos Espinhais/lesões , Animais , Cromatografia Líquida , Regulação da Expressão Gênica , Hiperalgesia/etiologia , Masculino , Neuralgia/etiologia , Medição da Dor , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Fatores de Tempo
12.
Chem Biol Interact ; 353: 109803, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34998817

RESUMO

The fact that neuropathic pain (NP) has no effective therapy and is frequently accompanied by psychiatric comorbidities is well established. Aberrant neuroinflammation plays an important role in the development and maintenance of NP. HDAC6 inhibitors have been demonstrated to ameliorate mechanical allodynia brought on by chemotherapy and peripheral nerve damage. However, its pharmacological mechanisms and its effects on NP-related mental disorders have not been fully elucidated. The present study was dedicated to exploring the effects of ACY-1215 (a specific HDAC6 inhibitor) on neuroinflammation and behavioral abnormalities associated with NP. In this work, spinal nerve ligation (SNL) was performed as an NP model on rats. Mechanical allodynia, cognitive impairment, and depressive-like behavior caused by SNL were attenuated by continuous intraperitoneal injection of ACY-1215. Moreover, ACY-1215 administration suppressed SNL-induced neuroinflammatory responses (including microgliosis, the elevation of pro-inflammatory factors IL-1ß and TNF-α) in ligation of the ipsilateral spinal dorsal horn (iSDH), hippocampus (HPC) and prefrontal cortex (PFC). Mechanistically, MyD88-dependent pro-inflammatory pathways (MyD88/NF-κB and MyD88/ERK) were activated in the iSDH following SNL and were inhibited by ACY-1215. Moreover, ACY-1215 enhanced the acetylation modification of MyD88 and inhibited the SNL-induced elevation of MyD88 without affecting its transcription in the iSDH. These findings suggest that pharmacological inhibition of HDAC6 can ameliorate NP and its psychiatric complications through modulating neuroinflammation, in part by blocking the MyD88-mediated pro-inflammatory pathways. The possible mechanism is that ACY-1215 prevents the elevation of MyD88 reactivity by increasing its acetylation level. Notably, neither SNL nor ACY-1215 significantly altered MyD88 expression in HPC and PFC, indicating differentiated pro-inflammatory mechanisms in the supraspinal neural regions.


Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Neuralgia/tratamento farmacológico , Traumatismos dos Nervos Periféricos/patologia , Pirimidinas/uso terapêutico , Animais , Hipocampo/metabolismo , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Interleucina-1beta/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/metabolismo , Neuralgia/etiologia , Traumatismos dos Nervos Periféricos/complicações , Córtex Pré-Frontal/metabolismo , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Nervos Espinhais/cirurgia
13.
Cell Mol Neurobiol ; 42(2): 389-417, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33030712

RESUMO

Gut inflammation or injury causes intestinal hypersensitivity (IHS) and hyperalgesia, which can persist after the initiating pathology resolves, are often referred to somatic regions and exacerbated by psychological stress, anxiety or depression, suggesting the involvement of both the spinal cord and the brain. The supraspinal mechanisms of IHS remain to be fully elucidated, however, over the last decades the series of intestinal pathology-associated neuroplastic changes in the brain has been revealed, being potentially responsible for the phenomenon. This paper reviews current clinical and experimental data, including the authors' own findings, on these functional, structural, and neurochemical/molecular changes within cortical, subcortical and brainstem regions processing and modulating sensory signals from the gut. As concluded in the review, IHS can develop and maintain due to the bowel inflammation/injury-induced persistent hyperexcitability of viscerosensory brainstem and thalamic nuclei and sensitization of hypothalamic, amygdala, hippocampal, anterior insular, and anterior cingulate cortical areas implicated in the neuroendocrine, emotional and cognitive modulation of visceral sensation and pain. An additional contribution may come from the pathology-triggered dysfunction of the brainstem structures inhibiting nociception. The mechanism underlying IHS-associated regional hyperexcitability is enhanced NMDA-, AMPA- and group I metabotropic receptor-mediated glutamatergic neurotransmission in association with altered neuropeptide Y, corticotropin-releasing factor, and cannabinoid 1 receptor signaling. These alterations are at least partially mediated by brain microglia and local production of cytokines, especially tumor necrosis factor α. Studying the IHS-related brain neuroplasticity in greater depth may enable the development of new therapeutic approaches against chronic abdominal pain in inflammatory bowel disease.


Assuntos
Hormônio Liberador da Corticotropina , Hiperalgesia , Humanos , Hiperalgesia/etiologia , Plasticidade Neuronal , Nociceptividade , Dor/complicações
14.
J Pain ; 23(2): 305-317, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34500109

RESUMO

The aim of the study was to determine whether transcranial direct current stimulation (tDCS) reduced pain and signs of central sensitization induced by low frequency electrical stimulation in healthy volunteers. Thirty-nine participants received tDCS stimulation under 4 different conditions: anodal tDCS of the primary motor cortex (M1), anodal tDCS of the dorsolateral prefrontal cortex (DLPFC), anodal tDCS over M1 and DLPFC concurrently, and sham tDCS. Participants were blind to the tDCS condition. The order of the conditions was randomized among participants. Pain ratings to pinpricks, the current level that evoked moderate pain, and pain induced by low frequency electrical stimulation were assessed in the forearm by an experimenter who was blind to the tDCS conditions. Anodal tDCS at M1 increased the current level that evoked moderate pain compared to sham and other conditions. Anodal tDCS of DLPFC completely abolished secondary hyperalgesia. Unexpectedly, however, concurrent anodal tDCS over M1 and DLPFC did not reduce pain or hyperalgesia more than M1 alone or DLPFC alone. Overall, these findings suggest that anodal tDCS over M1 suppresses pain, and that anodal tDCS over DLPFC modulates secondary hyperalgesia (a sign of central sensitization) in healthy participants. PERSPECTIVE: Anodal transcranial current stimulation (atDCS) at the left motor cortex and the dorsolateral prefrontal cortex increased the electrically-evoked pain threshold and reduced secondary hyperalgesia in healthy participants. Replication of this study in chronic pain populations may open more avenues for chronic pain treatment.


Assuntos
/fisiologia , Hiperalgesia/terapia , Córtex Motor/fisiologia , Limiar da Dor/fisiologia , Estimulação Transcraniana por Corrente Contínua , Adulto , Estimulação Elétrica , Feminino , Voluntários Saudáveis , Humanos , Hiperalgesia/etiologia , Masculino , Avaliação de Resultados em Cuidados de Saúde
15.
Neuropharmacology ; 205: 108909, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34875284

RESUMO

Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory nervous system. It is accompanied by neuronal and non-neuronal alterations, including alterations in intracellular second messenger pathways. Cellular levels of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) are regulated by phosphodiesterase (PDE) enzymes. Here, we studied the impact of PDE inhibitors (PDEi) in a mouse model of peripheral nerve injury induced by placing a cuff around the main branch of the sciatic nerve. Mechanical hypersensitivity, evaluated using von Frey filaments, was relieved by sustained treatment with the non-selective PDEi theophylline and ibudilast (AV-411), with PDE4i rolipram, etazolate and YM-976, and with PDE5i sildenafil, zaprinast and MY-5445, but not by treatments with PDE1i vinpocetine, PDE2i EHNA or PDE3i milrinone. Using pharmacological and knock-out approaches, we show a preferential implication of delta opioid receptors in the action of the PDE4i rolipram and of both mu and delta opioid receptors in the action of the PDE5i sildenafil. Calcium imaging highlighted a preferential action of rolipram on dorsal root ganglia non-neuronal cells, through PDE4B and PDE4D inhibition. Rolipram had anti-neuroimmune action, as shown by its impact on levels of the pro-inflammatory cytokine tumor necrosis factor-α (TNFα) in the dorsal root ganglia of mice with peripheral nerve injury, as well as in human peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharides. This study suggests that PDEs, especially PDE4 and 5, may be targets of interest in the treatment of neuropathic pain.


Assuntos
Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Traumatismos dos Nervos Periféricos/complicações , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Hiperalgesia/etiologia , Camundongos , Neuralgia/etiologia , Rolipram/farmacologia
16.
Pain ; 163(3): e463-e475, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34174041

RESUMO

ABSTRACT: Chronic pain is often accompanied by anxiety and depression disorders. Amygdala nuclei play important roles in emotional responses, fear, depression, anxiety, and pain modulation. The exact mechanism of how amygdala neurons are involved in pain and anxiety is not completely understood. The central nucleus of the amygdala contains 2 major subpopulations of GABAergic neurons that express somatostatin (SOM+) or protein kinase Cδ (PKCδ+). In this study, we found about 70% of phosphorylated ERK-positive neurons colocalized with PKCδ+ neurons in the formalin-induced pain model in mice. Optogenetic activation of PKCδ+ neurons was sufficient to induce mechanical hyperalgesia without changing anxiety-like behavior in naïve mice. Conversely, chemogenetic inhibition of PKCδ+ neurons significantly reduced the mechanical hyperalgesia in the pain model. By contrast, optogenetic inhibition of SOM+ neurons induced mechanical hyperalgesia in naïve mice and increased phosphorylated ERK-positive neurons mainly in PKCδ+ neurons. Optogenetic activation of SOM+ neurons slightly reduced the mechanical hyperalgesia in the pain model but did not change the mechanical sensitivity in naïve mice. Instead, it induced anxiety-like behavior. Our results suggest that the PKCδ+ and SOM+ neurons in the central amygdala exert different functions in regulating pain-like and anxiety-like behaviors in mice.


Assuntos
Núcleo Central da Amígdala , Dor Crônica , Animais , Ansiedade/etiologia , Núcleo Central da Amígdala/metabolismo , Dor Crônica/metabolismo , Neurônios GABAérgicos , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Camundongos
17.
Lasers Med Sci ; 37(2): 821-829, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33890191

RESUMO

This study aimed to investigate the central involvement of 5-HT1A receptors in the nociceptive behavior of mice submitted to the chronic constriction injury (CCI) of sciatic nerve and the subsequent application of photobiomodulation (PBM). Male mice (Swiss-albino) were submitted to CCI and subsequently received an infusion of WAY100635 (5-HT1A receptor antagonist) or intracerebroventricular saline (ICV), followed by infrared laser irradiation (808 nm), in continuous mode, with the power of 100 mW and a dose of 0 J/cm2 (control group) or 50 J/cm2. The thermal hyperalgesia was evaluated by hot plate test, while mechanical allodynia was evaluated by von Frey filaments. After CCI, animals showed a reduction in the nociceptive threshold (p<0.001) when compared to the sham group. In von Frey test, the CCI + saline + PBM 50 J/cm2 group showed an increase in nociceptive threshold (p<0.001) in all measurement moments in comparison with groups CCI + SALINE + PBM 0 J/cm2, CCI + WAY100635 + PBM 50 J/cm2, and CCI + WAY100635 + PBM 0 J/cm2. Similarly, in hot plate test, CCI + SALINE + PBM 50 J/cm2 group showed an increase in nociceptive threshold after application of PBM at 120 and 180 min. Because of the results found, it can be suggested the involvement of 5-HT1A receptors in the central nervous system, since WAY100635 was able to reverse the antinociceptive effect provided by PBM in animals submitted to CCI.


Assuntos
Neuralgia , Receptor 5-HT1A de Serotonina , Animais , Modelos Animais de Doenças , Hiperalgesia/etiologia , Hiperalgesia/radioterapia , Masculino , Camundongos , Neuralgia/radioterapia , Nervo Isquiático
18.
Pain ; 163(1): e49-e61, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33863858

RESUMO

ABSTRACT: Chronic pain is a highly prevalent symptom associated with the autoimmune disorder multiple sclerosis (MS). The central nucleus of the amygdala plays a critical role in pain processing and modulation. Neuropathic pain alters nociceptive signaling in the central amygdala, contributing to pain chronicity and opioid tolerance. Here, we demonstrate that activated microglia within the central amygdala disrupt nociceptive sensory processing and contribute to pain hypersensitivity in experimental autoimmune encephalomyelitis (EAE), the most frequently used animal model of MS. Male and female mice with EAE exhibited differences in microglial morphology in the central amygdala, which was associated with heat hyperalgesia, impaired morphine reward, and reduced morphine antinociception in females. Animals with EAE displayed a lack of morphine-evoked activity in cells expressing somatostatin within the central amygdala, which drive antinociception. Induction of focal microglial activation in naïve mice via injection of lipopolysaccharide into the central amygdala produced a loss of morphine analgesia in females, similar to as observed in EAE animals. Our data indicate that activated microglia within the central amygdala may contribute to the sexually dimorphic effects of morphine and may drive neuronal adaptations that lead to pain hypersensitivity in EAE. Our results provide a possible mechanism underlying the decreased efficacy of opioid analgesics in the management of MS-related pain, identifying microglial activation as a potential therapeutic target for pain symptoms in this patient population.


Assuntos
Analgesia , Núcleo Central da Amígdala , Encefalomielite Autoimune Experimental , Neuralgia , Analgésicos Opioides/uso terapêutico , Animais , Tolerância a Medicamentos , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/complicações , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Inflamação , Masculino , Camundongos , Morfina/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/etiologia
19.
Pain ; 163(5): e622-e633, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34382604

RESUMO

ABSTRACT: Prolotherapy is widely used in pain control and tissue repair in pain medicine. The classical mode is injection with hypertonic dextrose in muscle or perimysium. However, the analgesic mechanism is still not known. Here, we successfully established dextrose-mediated antinociception in a mouse model of fibromyalgia. The antinociceptive effects of dextrose injections were evaluated in a mouse model of fibromyalgia, in which bilateral chronic mechanical hyperalgesia was induced by unilateral intramuscular acid injection. The injectant (dextrose), dose (≥5%), and volume (>10 µL), but not osmolarity, were essential for the prolotherapy. Further studies showed that the activation of acid-sensing ion channel 1a (ASIC1a), neural activation, and the release of substance P from muscle afferents were required in the dextrose-induced reduction of mechanical hypersensitivity. Both pharmacological blockade and genetic deletion of ASIC1a or substance P as well as lidocaine abolished the dextrose-induced antinociception in mice with chronic hyperalgesia. Moreover, intramuscular dextrose injection induced phosphorylated extracellular signal-regulated kinase expression in dorsal root ganglion neurons expressing substance P; the phosphorylated extracellular signal-regulated kinase expression was inhibited by the ASIC1a antagonist PcTx1. The optimal settings for prolotherapy in fibromyalgia-like pain are dextrose dependent and volume dependent, and the peripheral antinociception involves ASIC1a and substance P signaling in muscle afferents. This study suggests a possible mechanism of action of dextrose prolotherapy in noninflammatory muscle pain such as fibromyalgia and provides insights into treating other types of chronic pain.


Assuntos
Analgesia , Fibromialgia , Proloterapia , Canais Iônicos Sensíveis a Ácido , Animais , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular , Fibromialgia/tratamento farmacológico , Glucose , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Camundongos , Mialgia/tratamento farmacológico , Substância P/uso terapêutico
20.
Pain Pract ; 22(2): 148-158, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34351685

RESUMO

OBJECTIVES: This study investigated the antinociceptive effects of co-administration of lithium chloride (LiCl) and vitamin E (Vit E) on chronic constriction injury (CCI)-induced peripheral neuropathy in male Wistar rats. It further explored the anti-inflammatory and neuroprotective properties of LiCl and Vit E, which may be complementary to the antinociceptive effects of the two substances. METHODS: Thirty-six male Wistar rats, 190.00 ± 10.00 g of body weight were randomly assigned to 6 experimental groups and administered with normal saline, Vit E, LiCl, or their combination, once daily for 21 days. CCI was used to induce neuropathic pain (NP) and mechanical allodynia was assessed using von Frey filaments and pinprick test. Open field maze (OFM) was used to assess the exploratory behavior. Biochemical parameters were assessed in the dorsal root ganglion after 21 days of treatment. RESULTS: Mechanical allodynia was developed in rats following CCI. Co-administration of LiCl and Vit E synergistically reduced mechanical hyperalgesia in rats which were significantly different compared with the single administration of either Vit E or LiCl. Combined doses of Vit E and LiCl significantly increases the explorative behavior in the OFM. CCI increased malondialdehyde (MDA), tumor necrotic factor-alpha (TNF-α), calcitonin gene-related polypeptide, calcium ion (Ca2+ ), and reduced superoxide dismutase (SOD) activities. Co-administration of LiCl and Vit E significantly reduced MDA, TNF-α, but increased SOD compared with ligated control. DISCUSSION: The findings revealed that the synergistic effects of the co-administration of Vit E and LiCl in ameliorating NP are mediated by their anti-inflammatory and antioxidant properties.


Assuntos
Antioxidantes , Neuralgia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Constrição , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Cloreto de Lítio/uso terapêutico , Masculino , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Ratos , Ratos Wistar , Vitamina E/uso terapêutico
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