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Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical allodynia. The role of skin mechanoreceptors in the development of mechanical allodynia is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aß axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin-keratinocyte specific BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia.
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Atopic dermatitis (AD) is predominantly characterized by intense itching, but concomitant skin pain is experienced by more than 40% of patients. Patients with AD display considerable somatosensory aberrations, including increased nerve sensitivity to itch stimuli (hyperknesis), perception of itch from innocuous stimuli (alloknesis), or perception of pain from innocuous stimuli (allodynia). This review summarizes the current understanding of the similarities and differences in the peripheral mechanisms underlying itch and pain in AD. These distinct yet reciprocal sensations share many similarities in the peripheral nervous system, including common mediators (such as serotonin, endothelin-1, IL-33, and thymic stromal lymphopoietin), receptors (such as members of the G protein-coupled receptor family and Toll-like receptors), and ion channels for signal transduction (such as certain members of the transient receptor potential [TRP] cation channels). Itch-responding neurons are also sensitive to pain stimuli. However, there are distinct differences between itch and pain signaling. For example, specific immune responses are associated with pain (type 1 and/or type 3 cytokines and certain chemokine C-C [CCL2, CCL5] and C-X-C [CXCL] motif ligands) and itch (type 2 cytokines, including IL-31, and periostin). The TRP melastatin channels TRPM2 and TRPM3 have a role in pain but no known role in itch. Activation of µ-opioid receptors is known to alleviate pain but exacerbate itch. Understanding the connection between itch and pain mechanisms may offer new insights into the treatment of chronic pain and itch in AD.
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Dermatite Atópica , Humanos , Dermatite Atópica/metabolismo , Prurido , Dor , Citocinas/metabolismo , Transdução de SinaisRESUMO
It is well-established that spinal microglia and peripheral macrophages play critical roles in the etiology of neuropathic pain; however, growing evidence suggests sex differences in pain hypersensitivity owing to microglia and macrophages. Therefore, it is crucial to understand sex- and androgen-dependent characteristics of pain-related myeloid cells in mice with nerve injury-induced neuropathic pain. To deplete microglia and macrophages, pexidartinib (PLX3397), an inhibitor of the colony-stimulating factor 1 receptor, was orally administered, and mice were subjected to partial sciatic nerve ligation (PSL). Following PSL induction, healthy male and female mice and male gonadectomized (GDX) mice exhibited similar levels of spinal microglial activation, peripheral macrophage accumulation, and mechanical allodynia. Treatment with PLX3397 significantly suppressed mechanical allodynia in normal males; this was not observed in female and GDX male mice. Sex- and androgen-dependent differences in the PLX3397-mediated preventive effects were observed on spinal microglia and dorsal root ganglia (DRG) macrophages, as well as in expression patterns of pain-related inflammatory mediators in these cells. Conversely, no sex- or androgen-dependent differences were detected in sciatic nerve macrophages, and inhibition of peripheral CC-chemokine receptor 5 prevented neuropathic pain in both sexes. Collectively, these findings demonstrate the presence of considerable sex- and androgen-dependent differences in the etiology of neuropathic pain in spinal microglia and DRG macrophages but not in sciatic nerve macrophages. Given that the mechanisms of neuropathic pain may differ among experimental models and clinical conditions, accumulating several lines of evidence is crucial to comprehensively clarifying the sex-dependent regulatory mechanisms of pain.
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Microglia , Neuralgia , Pirróis , Caracteres Sexuais , Animais , Masculino , Feminino , Camundongos , Neuralgia/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Pirróis/farmacologia , Aminopiridinas/farmacologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Nervo Isquiático/lesões , Nervo Isquiático/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos dos Nervos Periféricos/complicações , Traumatismos dos Nervos Periféricos/metabolismo , Modelos Animais de DoençasRESUMO
Abdominal visceral pain is a predominant symptom in patients with chronic pancreatitis (CP); however, the underlying mechanism of pain in CP remains elusive. We hypothesized that astrocytes in the hypothalamic paraventricular nucleus (PVH) contribute to CP pain pathogenesis. A mouse model of CP was established by repeated intraperitoneal administration of caerulein to induce abdominal visceral pain. Abdominal mechanical stimulation, open field and elevated plus maze tests were performed to assess visceral pain and anxiety-like behavior. Fiber photometry, brain slice Ca2+ imaging, electrophysiology, and immunohistochemistry were used to investigate the underlying mechanisms. Mice with CP displayed long-term abdominal mechanical allodynia and comorbid anxiety, which was accompanied by astrocyte glial fibrillary acidic protein reactivity, elevated Ca2+ signaling, and astroglial glutamate transporter-1 (GLT-1) deficits in the PVH. Specifically, reducing astrocyte Ca2+ signaling in the PVH via chemogenetics significantly rescued GLT-1 deficits and alleviated mechanical allodynia and anxiety in mice with CP. Furthermore, we found that GLT-1 deficits directly contributed to the hyperexcitability of VGLUT2PVH neurons in mice with CP, and that pharmacological activation of GLT-1 alleviated the hyperexcitability of VGLUT2PVH neurons, abdominal visceral pain, and anxiety in these mice. Taken together, our data suggest that dysfunctional astrocyte glutamate uptake in the PVH contributes to visceral pain and anxiety in mice with CP, highlighting GLT-1 as a potential therapeutic target for chronic pain in patients experiencing CP.
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While neural oscillations play a critical role in sensory perception, it remains unclear how these rhythms function under conditions of neuropathic allodynia. Recent studies demonstrated that the anterior cingulate cortex (ACC) is associated with the affective-aversive component of pain, and plasticity changes in this region are closely linked to abnormal allodynic sensations. Here, to study the mechanisms of allodynia, we recorded local field potentials (LFPs) in the bilateral ACC of awake-behaving rats and compared the spectral power and center frequency of brain oscillations between healthy and CCI (chronic constriction injury) induced neuropathic pain conditions. Our results indicated that activation of the ACC occurs bilaterally in the presence of neuropathic pain, similar to the healthy condition. Furthermore, CCI affects both spontaneous and stimulus-induced activity of ACC neurons. Specifically, we observed an increase in spontaneous beta activity after nerve injury compared to the healthy condition. By stimulating operated or unoperated paws, we found more intense event-related desynchronization (ERD) responses in the theta, alpha, and beta frequency bands and faster alpha center frequency after CCI compared to before CCI. Although the behavioral manifestation of allodynia was more pronounced in the operated paw than the unoperated paw following CCI, there was no significant difference in the center frequency and ERD responses observed in the ACC between stimulation of the operated and unoperated limbs. Our findings offer evidence supporting the notion that aberrancies in ACC oscillations may contribute to the maintenance and development of neuropathic allodynia.
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Neuralgia , Traumatismos do Sistema Nervoso , Ratos , Animais , Hiperalgesia , Giro do Cíngulo , Ratos Sprague-Dawley , Neurônios/fisiologiaRESUMO
Background: Recent studies have demonstrated that activated microglia were involved in the pathogenesis of central sensitization characterized by cutaneous allodynia in migraine. Activation of microglia is accompanied by increased expression of its receptors and release of inflammatory mediators. Acupuncture and its developed electroacupuncture (EA) have been recommended as an alternative therapy for migraine and are widely used for relieving migraine-associated pain. However, it remains rare studies that show whether EA exerts anti-migraine effects via inhibiting microglial activation related to a release of microglial receptors and the inflammatory pathway. Therefore, this study aimed to investigate EA' ability to ameliorate central sensitization via modulation of microglial activation, microglial receptor, and inflammatory response using a rat model of migraine induced by repeated epidural chemical stimulation. Methods: In the present study, a rat model of migraine was established by epidural repeated inflammatory soup (IS) stimulation and treated with EA at Fengchi (GB20) and Yanglingquan (GB34) and acupuncture at sham-acupoints. Pain hypersensitivity was further determined by measuring the mechanical withdrawal threshold using the von-Frey filament. The changes in c-Fos and ionized calcium binding adaptor molecule 1 (Ibal-1) labeled microglia in the trigeminal nucleus caudalis (TNC) were examined by immunflurescence to assess the central sensitization and whether accompanied with microglia activation. In addition, the expression of Ibal-1, microglial purinoceptor P2X4, and its associated inflammatory signaling pathway mediators, including interleukin (IL)-1ß, NOD-like receptor protein 3 (NLRP3), and Caspase-1 in the TNC were investigated by western blot and real-time polymerase chain reaction analysis. Results: Allodynia increased of c-Fos, and activated microglia were observed after repeated IS stimulation. EA alleviated the decrease in mechanical withdrawal thresholds, reduced the activation of c-Fos and microglia labeled with Ibal-1, downregulated the level of microglial purinoceptor P2X4, and limited the inflammatory response (NLRP3/Caspase-1/IL-1ß signaling pathway) in the TNC of migraine rat model. Conclusions: Our results indicate that the anti-hyperalgesia effects of EA ameliorate central sensitization in IS-induced migraine by regulating microglial activation related to P2X4R and NLRP3/IL-1ß inflammatory pathway.
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Modelos Animais de Doenças , Eletroacupuntura , Hiperalgesia , Inflamação , Microglia , Transtornos de Enxaqueca , Ratos Sprague-Dawley , Receptores Purinérgicos P2X4 , Animais , Eletroacupuntura/métodos , Receptores Purinérgicos P2X4/metabolismo , Microglia/metabolismo , Hiperalgesia/terapia , Hiperalgesia/metabolismo , Transtornos de Enxaqueca/terapia , Transtornos de Enxaqueca/metabolismo , Masculino , Inflamação/metabolismo , Inflamação/patologia , Inflamação/terapia , Sensibilização do Sistema Nervoso Central/fisiologia , Ratos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the community suffer persistent neuropathic pain symptoms because current drug therapies may be suboptimal so there is a need for new therapeutic modalities. This study investigated the neuroprotective flavonoid, 6-methoxyflavone (6MF), as a potential therapeutic agent and gabapentin as the standard comparator, against neuropathic models. Thus, neuropathic-like states were induced in Sprague-Dawley rats using sciatic nerve chronic constriction injury (CCI) mononeuropathy and systemic administration of streptozotocin (STZ) to induce polyneuropathy. Subsequent behaviors reflecting allodynia, hyperalgesia, and vulvodynia were assessed and any possible motoric side-effects were evaluated including locomotor activity, as well as rotarod discoordination and gait disruption. 6MF (25-75 mg/kg) antagonized neuropathic-like nociceptive behaviors including static- (pressure) and dynamic- (light brushing) hindpaw allodynia plus heat/cold and pressure hyperalgesia in the CCI and STZ models. 6MF also reduced static and dynamic components of vulvodynia in the STZ induced polyneuropathy model. Additionally, 6MF reversed CCI and STZ suppression of locomotor activity and rotarod discoordination, suggesting a beneficial activity on motor side effects, in contrast to gabapentin. Hence, 6MF possesses anti-neuropathic-like activity not only against different nociceptive modalities but also impairment of motoric side effects.
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Flavonas , Hiperalgesia , Neuralgia , Ratos Sprague-Dawley , Animais , Ratos , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Flavonas/farmacologia , Flavonas/uso terapêutico , Hiperalgesia/tratamento farmacológico , Masculino , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Gabapentina/farmacologia , Gabapentina/uso terapêutico , Nociceptividade/efeitos dos fármacos , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Feminino , Ácido gama-Aminobutírico/metabolismo , Aminas/farmacologia , Aminas/uso terapêutico , Nervo Isquiático/lesões , Nervo Isquiático/efeitos dos fármacos , Vulvodinia/tratamento farmacológico , Constrição , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêuticoRESUMO
Vestibulodynia is a complex pain disorder characterized by chronic discomfort in the vulvar region, often accompanied by tactile allodynia and spontaneous pain. In patients a depressive behaviour is also observed. In this study, we have used a model of vestibulodynia induced by complete Freund's adjuvant (CFA) focusing our investigation on the spinal cord neurons and microglia. We investigated tactile allodynia, spontaneous pain, and depressive-like behavior as key behavioral markers of vestibulodynia. In addition, we conducted in vivo electrophysiological recordings to provide, for the first time to our knowledge, the characterization of the spinal sacral neuronal activity in the L6-S1 dorsal horn of the spinal cord. Furthermore, we examined microglia activation in the L6-S1 dorsal horn using immunofluorescence, unveiling hypertrophic phenotypes indicative of neuroinflammation in the spinal cord. This represents a novel insight into the role of microglia in vestibulodynia pathology. To address the therapeutic aspect, we employed pharmacological interventions using GABApentin, amitriptyline, and PeaPol. Remarkably, all three drugs, also used in clinic, showed efficacy in alleviating tactile allodynia and depressive-like behavior. Concurrently, we also observed a normalization of the altered neuronal firing and a reduction of microglia hypertrophic phenotypes. In conclusion, our study provides a comprehensive understanding of the CFA-induced model of vestibulodynia, encompassing behavioral, neurophysiological and neuroinflammatory aspects. These data pave the way to investigate spinal cord first pain plasticity in vestibulodynia.
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Modelos Animais de Doenças , Adjuvante de Freund , Hiperalgesia , Microglia , Neurônios , Medula Espinal , Vulvodinia , Animais , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Camundongos , Hiperalgesia/fisiopatologia , Hiperalgesia/metabolismo , Vulvodinia/fisiopatologia , Vulvodinia/metabolismo , Feminino , Microglia/metabolismo , Neurônios/metabolismo , Doenças Neuroinflamatórias/fisiopatologia , Gabapentina/farmacologia , Amitriptilina/farmacologia , Depressão/fisiopatologia , Depressão/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Upregulation of soluble tumor necrosis factor (sTNF) cytokine signaling through TNF receptor 1 (TNFR1) and subsequent neuronal hyperexcitability are observed in both animal models and human chronic neuropathic pain (CNP). Previously, we have shown that estrogen modulates sTNF/TNFR1 signaling in CNP, which may contribute to female prevalence of CNP. The estrogen-dependent role of TNFR1-mediated supraspinal neuronal circuitry in CNP remains unknown. In this study, we interrogated the intersect between supraspinal TNFR1 mediated neuronal signaling and sex specificity by selectively removing TNFR1 in Nex + neurons in adult mice (NexCreERT2::TNFR1f/f). We determined that mechanical hypersensitivity induced by chronic constriction injury (CCI) decreases over time in males, but not in females. Subsequently, we investigated two downstream pathways, p38MAPK and NF-κB, important in TNFR1 signaling and injury response. We detected p38MAPK and NF-κB activation in male cortical tissue; however, p38MAPK phosphorylation was reduced in NexCreERT2::TNFR1f/f males. We observed a similar recovery from acute pain in male mice following CCI when p38αMAPK was knocked out of supraspinal Nex + neurons (NexCreERT2::p38αMAPKf/f), while chronic pain developed in female mice. To explore the intersection between estrogen and inflammation in CNP we used a combination therapy of an estrogen receptor ß (ER ß) inhibitor with a sTNF/TNFR1 or general p38MAPK inhibitor. We determined both combination therapies lends therapeutic relief to females following CCI comparable to the response evaluated in male mice. These data suggest that TNFR1/p38αMAPK signaling in Nex + neurons in CNP is male-specific and lack of therapeutic efficacy following sTNF inhibition in females is due to ER ß interference. These studies highlight sex-specific differences in pathways important to pain chronification and elucidate potential therapeutic strategies that would be effective in both sexes.
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Dor Crônica , Estrogênios , Neuralgia , Neurônios , Receptores Tipo I de Fatores de Necrose Tumoral , Transdução de Sinais , Animais , Neuralgia/metabolismo , Masculino , Feminino , Camundongos , Estrogênios/metabolismo , Estrogênios/farmacologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Neurônios/metabolismo , Dor Crônica/metabolismo , Transdução de Sinais/fisiologia , NF-kappa B/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Hiperalgesia/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) is a major challenge for cancer patients who undergo chemotherapy with paclitaxel. Therefore, finding effective therapies for CIPN is crucial. Glatiramer acetate is used to treat multiple sclerosis that exerts neuroprotective properties in various studies. We hypothesized that glatiramer acetate could also improve the paclitaxel-induced peripheral neuropathy. We used a rat model of paclitaxel (2 mg/kg/every other day for 7 doses)-induced peripheral neuropathy. Rats were treated with either different doses of glatiramer acetate (1, 2, 4 mg/kg/day) or its vehicle for 14 days in separate groups. The mechanical and thermal sensitivity of the rats by using the Von Frey test and the Hot Plate test, respectively, were assessed during the study. The levels of oxidative stress (malondialdehyde and superoxide dismutase), inflammatory markers (TNF-α, IL-10, NF-kB), and nerve damage (H&E and S100B staining) in the sciatic nerves of the rats were also measured at the end of study. Glatiramer acetate (2 and 4 mg/kg) exerted beneficial effects on thermal and mechanical allodynia tests. It also modulated the inflammatory response by reducing TNF-α and NF-κB levels, enhancing IL-10 production, and improving the oxidative stress status by lowering malondialdehyde and increasing superoxide dismutase activity in the sciatic nerve of the rats. Furthermore, glatiramer acetate enhanced nerve conduction velocity in all treatment groups. Histological analysis revealed that glatiramer acetate (2 and 4 mg/kg) prevented paclitaxel-induced damage to the nerve structure. These results suggest that glatiramer acetate can alleviate the peripheral neuropathy induced by paclitaxel.
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Paclitaxel , Doenças do Sistema Nervoso Periférico , Humanos , Ratos , Animais , Paclitaxel/toxicidade , Acetato de Glatiramer/uso terapêutico , Acetato de Glatiramer/farmacologia , Interleucina-10 , Citocinas/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/prevenção & controle , Estresse Oxidativo , Hiperalgesia/induzido quimicamente , Superóxido Dismutase/metabolismo , Malondialdeído/farmacologiaRESUMO
Diabetic neuropathic pain is one of the most devasting disorders of peripheral nervous system. The loss of GABAergic inhibition is associated with the development of painful diabetic neuropathy. The current study evaluated the potential of 3-Hydroxy-2-methoxy-6-methyl flavone (3-OH-2'MeO6MF), to ameliorate peripheral neuropathic pain using an STZ-induced hyperglycemia rat model. The pain threshold was assessed by tail flick, cold, mechanical allodynia, and formalin test on days 0, 14, 21, and 28 after STZ administration accompanied by evaluation of several biochemical parameters. Administration of 3-OH-2'-MeO6MF (1,10, 30, and 100 mg/kg, i.p) significantly enhanced the tail withdrawal threshold in tail-flick and tail cold allodynia tests. 3-OH-2'-MeO6MF also increased the paw withdrawal threshold in mechanical allodynia and decreased paw licking time in the formalin test. Additionally, 3-OH-2'-MeO6MF also attenuated the increase in concentrations of myeloperoxidase (MPO), thiobarbituric acid reactive substances (TBARS), nitrite, TNF-α, and IL 6 along with increases in glutathione (GSH). Pretreatment of pentylenetetrazole (PTZ) (40 mg/kg, i.p.) abolished the antinociceptive effect of 3-OH-2'-MeO6MF in mechanical allodynia. Besides, the STZ-induced alterations in the GABA concentration and GABA transaminase activity attenuated by 3-OH-2'-MeO6MF treatment suggest GABAergic mechanisms. Molecular docking also authenticates the involvement of α2ß2γ2L GABA-A receptors and GABA-T enzyme in the antinociceptive activities of 3-OH-2'-MeO6MF.
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Diabetes Mellitus , Neuropatias Diabéticas , Flavonas , Neuralgia , Ratos , Animais , Hiperalgesia/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Estreptozocina , Simulação de Acoplamento Molecular , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/complicações , Analgésicos/farmacologia , Ácido gama-Aminobutírico/farmacologia , Flavonas/farmacologia , Flavonas/uso terapêutico , BiomarcadoresRESUMO
BACKGROUND: To date, a number of studies on migraine have cross-sectionally evaluated sensory sensitivity with aversion thresholds/scores along the migraine cycle, reporting a decreased tolerance to sensory stimuli in different sensory modalities. Our hypothesis was that patients with migraine would exhibit heightened sensitivity to sound, light, touch and smell on days where they reported greater headache intensity. METHODS: This is an exploratory, longitudinal study, carried out over the course of 27 days. Aversion thresholds or scores to sound, light, touch and smell were quantified in six patients with migraine (11.33 ± 6.53 headache days/month). RESULTS: Patients reported an increased sensitivity to light (padj = 0.0297), touch (padj = 0.0077), and smell (padj = 0.0201) on days with higher headache intensity. However, a greater sensitivity to sound on days with higher headache intensity was only reported when anxiety levels were high (padj = 1.4e-06). Interestingly, variable levels of tolerance to bothersome light over time can also influence the correlation between light sensitivity and headache intensity (padj = 1.4e-06). CONCLUSIONS: Based on the present findings, future longitudinal studies evaluating sensory threshold changes along the migraine cycle in patients with migraine should account for the increased tolerance to bothersome light over time as well as the effect of anxiety on auditory sensitivity.
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Transtornos de Enxaqueca , Percepção do Tato , Humanos , Estudos Longitudinais , Cefaleia , Limiar SensorialRESUMO
BACKGROUND: Cigarette smoking is commonly reported among chronic pain patients in the clinic. Although chronic nicotine exposure is directly linked to nociceptive hypersensitivity in rodents, underlying neurobiological mechanisms remain unknown. METHODS: Multi-tetrode recordings in freely moving mice were used to test the activity of dopaminergic projections from the ventral tegmental area (VTA) to pyramidal neurones in the anterior cingulate cortex (ACC) in chronic nicotine-treated mice. The VTAâACC dopaminergic pathway was inhibited by optogenetic manipulation to detect chronic nicotine-induced allodynia (pain attributable to a stimulus that does not normally provoke pain) assessed by von Frey monofilaments (force units in g). RESULTS: Allodynia developed concurrently with chronic (28-day) nicotine exposure in mice (0.36 g [0.0141] vs 0.05 g [0.0018], P<0.0001). Chronic nicotine activated dopaminergic projections from the VTA to pyramidal neurones in the ACC, and optogenetic inhibition of VTA dopaminergic terminals in the ACC alleviated chronic nicotine-induced allodynia in mice (0.06 g [0.0064] vs 0.28 g [0.0428], P<0.0001). Moreover, optogenetic inhibition of Drd2 dopamine receptor signalling in the ACC attenuated nicotine-induced allodynia (0.07 g [0.0082] vs 0.27 g [0.0211], P<0.0001). CONCLUSIONS: These findings implicate a role of Drd2-mediated dopaminergic VTAâACC pathway signalling in chronic nicotine-elicited allodynia.
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Giro do Cíngulo , Nicotina , Humanos , Camundongos , Animais , Nicotina/farmacologia , Hiperalgesia/induzido quimicamente , Dopamina/metabolismo , DorRESUMO
This study investigated the effects of pregabalin on microglial differentiation in rats with neuropathic pain (NP) induced by sciatic nerve ligation and transection. After confirming NP, the rats were randomly allocated to either a pregabalin or control group. The pregabalin group received intraperitoneal injections of 10 mg/kg pregabalin, while the control group received an equivalent volume of normal saline following surgery. On postoperative day 28, neuronal damage, microglial activity, and microglial differentiation were assessed. The pregabalin group exhibited significantly less neuronal damage compared to the control group, along with a significant decrease in activated microglial expression in both the brain and spinal cord. Pregabalin treatment also significantly altered the microglial phenotype expression, with a decrease in the M1 phenotype percentage and an increase in the M2 phenotype percentage in both the brain (M1 phenotype: 43.52 ± 12.16% and 18.00 ± 8.57% in the control and pregabalin groups, respectively; difference: 27.26 [15.18-42.10], p = 0.002; M2 phenotype: 16.88 ± 6.47% and 39.63 ± 5.82% in the control and pregabalin groups, respectively; difference 22.04 [17.17-32.70], p < 0.001) and the spinal cord ipsilateral to nerve injury (M1 phenotype: 44.35 ± 12.12% and 13.78 ± 5.39% in the control and pregabalin groups, respectively; difference 30.46 [21.73-44.45], p < 0.001; M2 phenotype: 7.64 ± 3.91% and 33.66 ± 7.95% in the control and pregabalin groups, respectively; difference 27.41 [21.21-36.30], p < 0.001). Overall, pregabalin treatment significantly decreased the microglial M1 phenotype while increasing the microglial M2 phenotype in NP rats.
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Diferenciação Celular , Microglia , Neuralgia , Pregabalina , Animais , Pregabalina/farmacologia , Pregabalina/uso terapêutico , Microglia/efeitos dos fármacos , Microglia/patologia , Neuralgia/tratamento farmacológico , Neuralgia/patologia , Neuralgia/etiologia , Ratos , Diferenciação Celular/efeitos dos fármacos , Masculino , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Modelos Animais de Doenças , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Ratos Sprague-Dawley , Humanos , Encéfalo/efeitos dos fármacos , Encéfalo/patologiaRESUMO
BACKGROUND: A few patients report intense pain and other unpleasant sensations, such as burning, dysesthesia and hyperalgesia, after even brief exposure to the sun and in the absence of any skin lesion. Sometimes they also develop systemic symptoms, such as mild fever, fatigue, faintness and fainting. As a result, these patients carefully avoid even short-term sun exposure with a consequent severe negative impact on their lives. METHODS: We have reviewed the clinical findings and the results of photobiological investigations of 10 patients who presented this clinical picture. Six of these patients were previously described by our group with the diagnosis of sun pain. We have reviewed the similarities with other previously described disorders such as solar dysesthesia and PUVA pain and have evaluated possible pathogenetic mechanisms. RESULTS: During phototesting our patients experienced intense pain in the exposed area and in the surrounding skin, without any visible lesion, even with very low sub-erythemal doses. At follow-up, five patients were diagnosed with fibromyalgia, three with a major depressive disorder, one with bipolar syndrome and one with a conversion disorder. The pathogenesis remains unclear, but the use of a psychopharmacological treatment with antidepressants improved both the neuropsychiatric symptoms and sensitivity to the sun in most subjects. CONCLUSION: For patients with pain and other severe symptoms in the absence of skin lesions and clinical and laboratory manifestations of known photodermatoses, a neuropsychiatric evaluation should be suggested.
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Transtorno Depressivo Maior , Transtornos de Fotossensibilidade , Humanos , Parestesia/diagnóstico , Parestesia/etiologia , Luz Solar/efeitos adversos , Transtornos de Fotossensibilidade/diagnóstico , Transtornos de Fotossensibilidade/etiologia , Dor/etiologiaRESUMO
BACKGROUND: This meta-analysis aimed to explore the correlation between the different doses of remifentanil-based anaesthesia and postoperative pain in randomised trials. METHODS: The electronic databases including PubMed, Cochrane, clinical trial registries, and Google Scholar were searched up to November 2022 for randomised controlled trials (RCTs) that assessed the dose dependent efficacy of remifentanil for postoperative pain intensity and hyperalgesia. RESULTS: 31 studies involving 2019 patients were included for analysis. Compared with the high remifentanil dose administration, patients in low doses showed less postoperative pain intensity at 1-2 h (weighted mean differences (WMD): 0.60, 95% CI, 0.05 to 1.15), 3-8 h (WMD: 0.38, 95% CI, 0.00 to 0.75), 24 h (WMD: 0.26, 95% CI, 0.04 to 0.48) and 48 h (WMD: 0.32, 95% CI, 0.09 to 0.55). Remifentanil-free regimen failed to decrease the pain score at 24 h (WMD: 0.10, 95% CI, -0.10 to 0.30) and 48 h (WMD: 0.15, 95% CI, -0.22 to 0.52) in comparison with remifentanil-based anaesthesia. After excluding trials with high heterogeneity, the dose of the remifentanil regimen was closely correlated with the postoperative pain score (P=0.03). In addition, the dose of the remifentanil regimen was not associated with the incidence of postoperative nausea and vomiting (PONV) (P=0.37). CONCLUSIONS: Our meta-analysis reveals that the low dose of remifentanil infusion is recommendable for general anaesthesia maintenance. No evidence suggests that remifentanil-free regimen has superiority in reducing postoperative pain. Moreover, remifentanil doesn't have a dose dependent effect in initiating PONV. TRIAL REGISTRATION: The protocol of present study was registered with PROSPERO (CRD42022378360).
Assuntos
Dor Pós-Operatória , Náusea e Vômito Pós-Operatórios , Humanos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Anestesia Geral , Hiperalgesia , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Dor Pós-Operatória/induzido quimicamente , Náusea e Vômito Pós-Operatórios/induzido quimicamente , Remifentanil/administração & dosagem , Remifentanil/efeitos adversos , Remifentanil/uso terapêuticoRESUMO
BACKGROUND: Spinal cord injury (SCI) presents a major global health challenge, with rising incidence rates and substantial disability. Although progress has been made in understanding SCI's pathophysiology and early management, there is still a lack of effective treatments to mitigate long-term consequences. This study investigates the potential of sovateltide, a selective endothelin B receptor agonist, in improving clinical outcomes in an acute SCI rat model. METHODS: Thirty male Sprague-Dawley rats underwent sham surgery (group A) or SCI and treated with vehicle (group B) or sovateltide (group C). Clinical tests, including Basso, Beattie, and Bresnahan scoring, inclined plane, and allodynia testing with von Frey hair, were performed at various time points. Statistical analyses assessed treatment effects. RESULTS: Sovateltide administration significantly improved motor function, reducing neurological deficits and enhancing locomotor recovery compared with vehicle-treated rats, starting from day 7 post injury. Additionally, the allodynic threshold improved, suggesting antinociceptive properties. Notably, the sovateltide group demonstrated sustained recovery, and even reached preinjury performance levels, whereas the vehicle group plateaued. CONCLUSIONS: This study suggests that sovateltide may offer neuroprotective effects, enhancing neurogenesis and angiogenesis. Furthermore, it may possess anti-inflammatory and antinociceptive properties. Future clinical trials are needed to validate these findings, but sovateltide shows promise as a potential therapeutic strategy to improve functional outcomes in SCI. Sovateltide, an endothelin B receptor agonist, exhibits neuroprotective properties, enhancing motor recovery and ameliorating hyperalgesia in a rat SCI model. These findings could pave the way for innovative pharmacological interventions for SCI in clinical settings.
RESUMO
Cannabidiol (CBD) is a substance that exerts several therapeutic actions, including analgesia. CBD is generally administered orally, but its poor water solubility and metabolism impair its bioavailability. Thus, the development of molecules with better pharmacokinetic profile from cannabidiol becomes an interesting strategy for the design of novel analgesic drugs for the relief of painful conditions that are difficult to manage clinically, such as neuropathic pain. In the present study, an unprecedented analogue of CBD (1) was synthesized and some of its physicochemical properties were evaluated inâ silico as well as its stability in an acid medium. Additionally, its effect was investigated in a model of neuropathic pain induced by the chemotherapy drug paclitaxel in mice, in comparison with cannabidiol itself. Cannabidiol (20â mg/kg), pregabalin (30â mg/kg), or analogue 1 (5, 10, and 20â mg/kg), administered on the 14th day after the first administration of paclitaxel, attenuated the mechanical allodynia of the sensitized animals. The antinociceptive activity of analogue 1 was attenuated by previous administration of a cannabinoid CB1 receptor antagonist, AM 251, which indicates that its mechanism of action is related to the activation of CB1 receptors. In conclusion, the CBD analogue 1 developed in this study shows great potential to be used in the treatment of neuropathic pain.
Assuntos
Canabidiol , Neuralgia , Camundongos , Animais , Canabidiol/efeitos adversos , Modelos Animais de Doenças , Neuralgia/tratamento farmacológico , Neuralgia/induzido quimicamente , Paclitaxel/farmacologia , Analgésicos/farmacologia , Analgésicos/uso terapêuticoRESUMO
The information provided from the papers reviewed here about the role of epigenetics in chronic craniofacial neuropathic pain is critically important because epigenetic dysregulation during the development and maintenance of chronic neuropathic pain is not yet well characterized, particularly for craniofacial pain. We have noted that gene expression changes reported vary depending on the nerve injury model and the reported sample collection time point. At a truly chronic timepoint of 10 weeks in our model of chronic neuropathic pain, functional groupings of genes examined include those potentially contributing to anti-inflammation, nerve repair/regeneration, and nociception. Genes altered after treatment with the epigenetic modulator LMK235 are discussed. All of these differentials are key in working toward the development of diagnosis-targeted therapeutics and likely for the timing of when the treatment is provided. The emphasis on the relevance of time post-injury is reiterated here.
Assuntos
Epigênese Genética , Histona Desacetilases , Neuralgia , Neuralgia/genética , Animais , Humanos , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Dor Crônica/genética , Dor Facial/genéticaRESUMO
Neurological symptoms associated with COVID-19, acute and long term, suggest SARS-CoV-2 affects both the peripheral and central nervous systems (PNS/CNS). Although studies have shown olfactory and hematogenous invasion into the CNS, coinciding with neuroinflammation, little attention has been paid to susceptibility of the PNS to infection or to its contribution to CNS invasion. Here we show that sensory and autonomic neurons in the PNS are susceptible to productive infection with SARS-CoV-2 and outline physiological and molecular mechanisms mediating neuroinvasion. Our infection of K18-hACE2 mice, wild-type mice, and golden Syrian hamsters, as well as primary peripheral sensory and autonomic neuronal cultures, show viral RNA, proteins, and infectious virus in PNS neurons, satellite glial cells, and functionally connected CNS tissues. Additionally, we demonstrate, in vitro, that neuropilin-1 facilitates SARS-CoV-2 neuronal entry. SARS-CoV-2 rapidly invades the PNS prior to viremia, establishes a productive infection in peripheral neurons, and results in sensory symptoms often reported by COVID-19 patients.