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1.
J Headache Pain ; 23(1): 8, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35033010

RESUMO

BACKGROUND: Astrocytic activation might play a significant role in the central sensitization of chronic migraine (CM). However, the temporal characteristics of the astrocytic activation in the trigeminal nucleus caudalis (TNC) and the molecular mechanism under the process remain not fully understood. Therefore, this study aims to investigate the duration and levels change of astrocytic activation and to explore the correlation between astrocytic activation and the levels change of cytokines release. METHODS: We used a mice model induced by recurrent dural infusion of inflammatory soup (IS). The variation with time of IS-induced mechanical thresholds in the periorbital and hind paw plantar regions were evaluated using the von Frey filaments test. We detected the expression profile of glial fibrillary acidic protein (GFAP) in the TNC through immunofluorescence staining and western blot assay. We also investigated the variation with time of the transcriptional levels of GFAP and ionized calcium binding adapter molecule 1 (Iba1) through RNAscope in situ hybridization analysis. Then, we detected the variation with time of cytokines levels in the TNC tissue extraction and serum, including c-c motif chemokine ligand 2 (CCL2), c-c motif chemokine ligand 5 (CCL5), c-c motif chemokine ligand 7 (CCL7), c-c motif chemokine ligand 12 (CCL12), c-x-c motif chemokine ligand 1 (CXCL1), c-x-c motif chemokine ligand 13 (CXCL13), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), macrophage colony-stimulating factor (M-CSF), interleukin 1beta (IL-1ß), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 17A (IL-17A). RESULTS: Recurrent IS infusion resulted in cutaneous allodynia in both the periorbital region and hind paw plantar, ranging from 5 d (after the second IS infusion) to 47 d (28 d after the last infusion) and 5 d to 26 d (7 d after the last infusion), respectively. The protein levels of GFAP and messenger ribonucleic acid (mRNA) levels of GFAP and Iba1 significantly increased and sustained from 20 d to 47 d (1 d to 28 d after the last infusion), which was associated with the temporal characteristics of astrocytic activation in the TNC. The CCL7 levels in the TNC decreased from 20 d to 47 d. But the CCL7 levels in serum only decreased on 20 d (1 d after the last infusion). The CCL12 levels in the TNC decreased on 22 d (3 d after the last infusion) and 33 d (14 d after the last infusion). In serum, the CCL12 levels only decreased on 22 d. The IL-10 levels in the TNC increased on 20 d. CONCLUSIONS: Our results indicate that the astrocytic activation generated and sustained in the IS-induced mice model from 1 d to 28 d after the last infusion and may contribute to the pathology through modulating CCL7, CCL12, and IL-10 release.


Assuntos
Transtornos de Enxaqueca , Núcleos do Trigêmeo , Animais , Sensibilização do Sistema Nervoso Central , Hiperalgesia/induzido quimicamente , Camundongos , Dor
2.
Invest Ophthalmol Vis Sci ; 63(1): 7, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34989761

RESUMO

Purpose: Dry eye-induced chronic ocular pain is also called ocular neuropathic pain. However, details of the pathogenic mechanism remain unknown. The purpose of this study was to elucidate the pathogenic mechanism of dry eye-induced chronic pain in the anterior eye area and develop a pathophysiology-based therapeutic strategy. Methods: We used a rat dry eye model with lacrimal gland excision (LGE) to elucidate the pathogenic mechanism of ocular neuropathic pain. Corneal epithelial damage, hypersensitivity, and hyperalgesia were evaluated on the LGE side and compared with the sham surgery side. We analyzed neuronal activity, microglial and astrocytic activity, α2δ-1 subunit expression, and inhibitory interneurons in the trigeminal nucleus. We also evaluated the therapeutic effects of ophthalmic treatment and chronic pregabalin administration on dry eye-induced ocular neuropathic pain. Results: Dry eye caused hypersensitivity and hyperalgesia on the LGE side. In the trigeminal nucleus of the LGE side, neuronal hyperactivation, transient activation of microglia, persistent activation of astrocytes, α2δ-1 subunit upregulation, and reduced numbers of inhibitory interneurons were observed. Ophthalmic treatment alone did not improve hyperalgesia. In contrast, continuous treatment with pregabalin effectively ameliorated hypersensitivity and hyperalgesia and normalized neural activity, α2δ-1 subunit upregulation, and astrocyte activation. Conclusions: These results suggest that dry eye-induced hypersensitivity and hyperalgesia are caused by central sensitization in the trigeminal nucleus with upregulation of the α2δ-1 subunit. Here, we showed that pregabalin is effective for treating dry eye-induced ocular neuropathic pain even after chronic pain has been established.


Assuntos
Analgésicos/administração & dosagem , Modelos Animais de Doenças , Síndromes do Olho Seco/fisiopatologia , Dor Ocular/fisiopatologia , Pregabalina/administração & dosagem , Administração Oftálmica , Animais , Astrócitos/patologia , Canais de Cálcio Tipo L/metabolismo , Doença Crônica , Córnea/inervação , Síndromes do Olho Seco/tratamento farmacológico , Dor Ocular/tratamento farmacológico , Ácido Hialurônico/administração & dosagem , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Microglia/patologia , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Neurônios/metabolismo , Neurônios/patologia , Soluções Oftálmicas , Ratos , Ratos Sprague-Dawley , Nervo Trigêmeo/metabolismo , Nervo Trigêmeo/patologia
3.
Arch Oral Biol ; 133: 105317, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34823152

RESUMO

OBJECTIVE: Cisplatin, a platinum-based anticancer drug, produces reactive oxygen species (ROS) in many cell types and induces mechanical allodynia in the hands and/or feet (chemotherapy-induced painful neuropathy: CIPN). In this study, we examined the possibility of inducing neuropathy in the oral region using oral keratinocytes and rats. METHODS: Human oral keratinocytes (HOKs) were used to evaluate ROS generation after cisplatin application by a ROS-reactive fluorescent assay. In rats, after cisplatin administrations (two times), the trigeminal ganglion (TG) was investigated by electron microscopy and quantitative RT-PCR. Using our proprietary assay system, oral pain-related behaviors were observed in cisplatin-treated rats. RESULTS: In rats, cisplatin administration reduced food intake and body weight. In electron microscopic analysis, glycogen granules in the TG were depleted following administration, although organelles were intact. In HOK cells, cisplatin significantly increased ROS generation with cell death, similar to glycolysis inhibitors. Cisplatin administration did not show any effects on Trpa1 mRNA levels in the TG. However, the same procedure induced hypersensitivity to mechanical stimulation and the TRPA1 agonist allyl isothiocyanate in the oral mucosa. Mechanical hypersensitivity was inhibited by the antioxidative drug α-lipoic acid and the TRPA1 antagonist HC-030031, similar to that of the hind paw. CONCLUSION: The present findings suggest that cisplatin induces TRPA1-mediated CIPN due to ROS generation in the oral region. This study will provide a better understanding of persistent oral pain in cancer patients.


Assuntos
Cisplatino , Doenças do Sistema Nervoso Periférico , Animais , Cisplatino/toxicidade , Humanos , Hiperalgesia/induzido quimicamente , Mucosa Bucal , Ratos , Canal de Cátion TRPA1
4.
Toxicon ; 206: 55-63, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34954133

RESUMO

Neuropathic pain in osteoarthritis is one of the reasons why the pain is difficult to treat, and P2X4R plays an important role in neuropathic pain. In addition, BoNT/A has been proven to have analgesic effects on both neuropathic pain and osteoarthritis, but its exact mechanism is still unknown. This study aims to investigate the relationship between the analgesic effect of BoNT/A on osteoarthritis and the expression of P2X4R in spinal cord microglia. The analgesic effect was compared between BoNT/A and compound betamethasone. Western blot analysis was used to examine the expression of P2X4R and BDNF proteins in the spinal cord. Immunohistochemistry was used to determine the cellular location of P2X4R. Mechanical allodynia and weight asymmetry were identified using the hind paw withdrawal threshold and weight bearing test. The results showed that intra-articular injection of MIA induced persistent mechanical allodynia and weight asymmetry in rats. Both BoNT/A and betamethasone could relieve pain behavior in rats, but BoNT/A had a more obvious effect and lasted longer. Furthermore, BoNT/A could reverse the MIA-induced overexpression of BDNF and P2X4R in the spinal dorsal horn. To sum up, BoNT/A is more effective than betamethasone in relieving MIA-induced osteoarthritis pain in rats, and its analgesic effect may be related to the regulation of P2X4R-mediated BDNF release in spinal microglia and the relief of neuropathic pain in osteoarthritis.


Assuntos
Neuralgia , Osteoartrite , Animais , Modelos Animais de Doenças , Hiperalgesia , Microglia , Neuralgia/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Medula Espinal
5.
Int J Mol Sci ; 22(24)2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34948328

RESUMO

Cyclooxygenase metabolizes dihomo-γ-linolenic acid and arachidonic acid to form prostaglandin (PG) E, including PGE1 and PGE2, respectively. Although PGE2 is well known to play an important role in the development and maintenance of hyperalgesia and allodynia, the role of PGE1 in pain is unknown. We confirm whether PGE1 induced pain using orofacial pain behavioral test in mice and determine the target molecule of PGE1 in TG neurons with whole-cell patch-clamp and immunohistochemistry. Intradermal injection of PGE1 to the whisker pads of mice induced a reduced threshold, enhancing the excitability of HCN channel-expressing trigeminal ganglion (TG) neurons. The HCN channel-generated inward current (Ih) was increased by 135.3 ± 4.8% at 100 nM of PGE1 in small- or medium-sized TG, and the action of PGE1 on Ih showed a concentration-dependent effect, with a median effective dose (ED50) of 29.3 nM. Adenylyl cyclase inhibitor (MDL12330A), 8-bromo-cAMP, and the EP2 receptor antagonist AH6809 inhibited PGE1-induced Ih. Additionally, PGE1-induced mechanical allodynia was blocked by CsCl and AH6809. PGE1 plays a role in mechanical allodynia through HCN2 channel facilitation via the EP2 receptor in nociceptive neurons, suggesting a potential therapeutic target in that PGE1 could be involved in pain as endogenous substances under inflammatory conditions.


Assuntos
Alprostadil/metabolismo , Gânglios Espinais/metabolismo , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Dor/metabolismo , Canais de Potássio/metabolismo , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Gânglio Trigeminal/metabolismo , Potenciais de Ação/fisiologia , Animais , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/metabolismo , Nociceptores/metabolismo , Medição da Dor/métodos
6.
Mol Pain ; 17: 17448069211058004, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34894846

RESUMO

Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes severe neuropathic pain typically encompassing cold allodynia and long-lasting mechanical allodynia. Endothelin has been shown to modulate nociceptive transmission in a variety of pain disorders. However, the action of endothelin varies greatly depending on many variables, including pain causes, receptor types (endothelin type A (ETA) and B (ETB) receptors) and organs (periphery and spinal cord). Therefore, in this study, we investigated the role of endothelin in a Sprague-Dawley rat model of oxaliplatin-induced neuropathic pain. Intraperitoneal administration of bosentan, a dual ETA/ETB receptor antagonist, effectively blocked the development or prevented the onset of both cold allodynia and mechanical allodynia. The preventive effects were exclusively mediated by ETA receptor antagonism. Intrathecal administration of an ETA receptor antagonist prevented development of long-lasting mechanical allodynia but not cold allodynia. In marked contrast, an intraplantar ETA receptor antagonist had a suppressive effect on cold allodynia but only had a partial and transient effect on mechanical allodynia. In conclusion, ETA receptor antagonism effectively prevented long-lasting mechanical allodynia through spinal and peripheral actions, while cold allodynia was prevented through peripheral actions.


Assuntos
Hiperalgesia , Neuralgia , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Oxaliplatina , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A
7.
Mol Pain ; 17: 17448069211061973, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34898326

RESUMO

BACKGROUND: While the PKCγ neurons in spinal dorsal horn play an indispensable part in neuropathic allodynia, the exact effect of PKCγ neurons of brain regions in neuropathic pain remains elusive. Mounting research studies have depicted that the anterior cingulate cortex (ACC) is closely linked with pain perception and behavior, the present study was designed to investigate the contribution of PKCγ neurons in ACC to neuropathic allodynia and pain-related emotion in newly developed Prkcg-P2A-Tdtomato mice. METHODS: The c-fos expression in response to innocuous stimulation was used to monitor the activity of PKCγ in CCI (chronic constriction injury of the sciatic nerve) induced neuropathic pain condition. Activating or silencing ACC PKCγ neurons by chemogenetics was applied to observe the changes of pain behavior. The excitability of ACC PKCγ neurons in normal and CCI mice was compared by patch-clamp whole-cell recordings. RESULTS: The PKCγ-Tdtomato neurons were mainly distributed in layer III-Vof ACC. The Tdtomato was mainly expressed in ACC pyramidal neurons demonstrated by intracellular staining. The c-fos expression in ACC PKCγ neurons in response to innocuous stimulation was obviously elevated in CCI mice. The patch clamp recordings showed that ACC PKCγ-Tdtomato neurons were largely activated in CCI mice. Chemogenetic activation of ACC PKCγ neurons in Prkcg-icre mice induced mechanical allodynia and pain-related aversive behavior, conversely, silencing them in CCI condition significantly reversed the mechanical allodynia and pain-related place aversive behavior. CONCLUSION: We conclude that the PKCγ neurons in ACC are closely linked with neuropathic allodynia and pain-related emotional behaviors.


Assuntos
Hiperalgesia , Neuralgia , Animais , Emoções , Giro do Cíngulo , Camundongos , Neurônios , Ratos , Ratos Sprague-Dawley
8.
J Headache Pain ; 22(1): 155, 2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34930118

RESUMO

BACKGROUND: The purpose of this narrative review is to examine the literature investigating a causal relationship between stress and migraine and evaluate its implications for managing migraine. METHODS: PubMed, PsycINFO and CINAHL were searched from 1988 to August 2021, identifying 2223 records evaluating the relationship between stress and migraine. Records were systematically screened. All potentially relevant records were thematically categorized into six mechanistic groups. Within each group the most recent reports providing new insights were cited. RESULTS: First, studies have demonstrated an association of uncertain causality between high stress loads from stressful life events, daily hassles or other sources, and the incidence of new-onset migraine. Second, major stressful life events seem to precede the transformation from episodic to chronic migraine. Third, there is some evidence for changes in levels of stress as a risk factor for migraine attacks. Research also suggests there may be a reversed causality or that stress-trigger patterns are too individually heterogeneous for any generalized causality. Fourth, migraine symptom burden seems to increase in a setting of stress, partially driven by psychiatric comorbidity. Fifth, stress may induce sensitization and altered cortical excitability, partially explaining attack triggering, development of chronic migraine, and increased symptom burden including interictal symptom burden such as allodynia, photophobia or anxiety. Finally, behavioral interventions and forecasting models including stress variables seem to be useful in managing migraine. CONCLUSION: The exact causal relationships in which stress causes incidence, chronification, migraine attacks, or increased burden of migraine remains unclear. Several individuals benefit from stress-oriented therapies, and such therapies should be offered as an adjuvant to conventional treatment and to those with a preference. Further understanding the relationship between stress, migraine and effective therapeutic options is likely to be improved by characterizing individual patterns of stress and migraine, and may in turn improve therapeutics.


Assuntos
Transtornos de Enxaqueca , Terapia Comportamental , Humanos , Hiperalgesia , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/terapia , Fatores de Risco
9.
Zhen Ci Yan Jiu ; 46(12): 1048-56, 2021 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-34970883

RESUMO

Hyperalgesia and functional plasticity are the important components of acupoint sensitization. Reveal of the neuromechanism of acupoint sensitization may play a positive role in promoting the development of acupuncturology in the world. The nociceptors, including Aδ and C subtypes distributing in the acupoint region and target organs, are responsible for the transmission of signals of peripheral noxious stimuli and acupuncture-liking stimulation to the dorsal horns of the spinal cord and supraspinal levels. A previous study reveals that the C type nociceptors are involved in the acupoint sensitization. Recent studies indicate that there exists a subtype of mechanical responsiveness in the C type receptors, named "silent nociceptor" which is awa-kened when diseases occur, being very similar to the dynamic sensitization characteristics of acupoints. Hence, we, in the present review, make a discussion about the role of C-type silent nociceptor in the hyperalgesia and functional plasticity of the sensitized acupoint according to previous studies and recent advances, so as to provide more ideas and opportunities for the investigation on the scientific characteristics of acupoints.


Assuntos
Terapia por Acupuntura , Nociceptores , Pontos de Acupuntura , Animais , Hiperalgesia/terapia , Corno Dorsal da Medula Espinal
10.
Zhonghua Yi Xue Za Zhi ; 101(43): 3581-3587, 2021 Nov 23.
Artigo em Chinês | MEDLINE | ID: mdl-34808752

RESUMO

Objective: To investigate the molecular mechanism of oxaliplatin-induced chemotherapy-induced peripheral neuropathic pain (CIPNP). Methods: A total of 16 male Sprague-Dawley rats of specific pathogen-free grade were randomly divided into two groups: oxaliplatin experimental group (2.4 mg/kg oxaliplatin dissolved in 5.0% glucose solution, n=8) and control group (equal volume 5% glucose solution, n=8). The rat model of CIPNP was established by continuous administration with oxaliplatin. In addition, mechanical allodynia, thermal hyperalgesia and cold hyperalgesia were measured and compared between the two groups. To explore the molecular mechanism of oxaliplatin-induced CIPNP, the gene expression of dorsal root ganglia (DRG) from the rat model of CIPNP was analyzed using RNA sequencing (RNA-Seq). Results: Mechanical and thermal hypersensitivity was exhibited on day 7 and a stronger hypersensitivity was observed on day 14. A total of 20 152 genes were quantified by RNA-Seq, and 379 differentially expressed genes (DEGs) were obtained with absolute fold change cut-offs ≥ 2 and P value<0.05. There were 7 genes (Npy, Car3, Cdkn1a, Nts, Prc1, Ms4a7 and Ecel1) that were involved in peripheral nerve injury-related neuropathic pain. Gene ontology (GO) functional enrichment analyses indicated that the DEGs induced by oxaliplatin were involved in oxygen transport, cell division, intermediate, centromere, oxygen transporter activity, oxygen binding. Moreover, the result of Kyoto Encyclopedia of genes and genomes (KEGG) analyses highlighted that the DEGs induced by oxaliplatin were involved in malaria, African trypanosomiasis, primary immunodeficiency, peroxisome proliferator activated receptor (PPAR) signaling pathway. Conclusion: Oxaliplatin induces CIPNP via pain-related genes and signaling pathways.


Assuntos
Neuralgia , Animais , Gânglios Espinais , Hiperalgesia/induzido quimicamente , Masculino , Neuralgia/induzido quimicamente , Oxaliplatina , Ratos , Ratos Sprague-Dawley
11.
Front Cell Infect Microbiol ; 11: 760076, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722345

RESUMO

In recent years, increasing studies have been conducted on the mechanism of gut microbiota in neuropsychiatric diseases and non-neuropsychiatric diseases. The academic community has also recognized the existence of the microbiota-gut-brain axis. Chronic pain has always been an urgent difficulty for human beings, which often causes anxiety, depression, and other mental symptoms, seriously affecting people's quality of life. Hyperalgesia is one of the main adverse reactions of chronic pain. The mechanism of gut microbiota in hyperalgesia has been extensively studied, providing a new target for pain treatment. Enterochromaffin cells, as the chief sentinel for sensing gut microbiota and its metabolites, can play an important role in the interaction between the gut microbiota and hyperalgesia through paracrine or neural pathways. Therefore, this systematic review describes the role of gut microbiota in the pathological mechanism of hyperalgesia, learns about the role of enterochromaffin cell receptors and secretions in hyperalgesia, and provides a new strategy for pain treatment by targeting enterochromaffin cells through restoring disturbed gut microbiota or supplementing probiotics.


Assuntos
Microbioma Gastrointestinal , Probióticos , Encéfalo , Células Enterocromafins , Humanos , Hiperalgesia , Qualidade de Vida
12.
Alcohol Res ; 41(1): 13, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34729286

RESUMO

People living with pain report drinking alcohol to relieve pain. Acute alcohol use reduces pain, and chronic alcohol use facilitates the emergence or exaggeration of pain. Recently, funding agencies and neuroscientists involved in basic research have turned their attention to understanding the neurobiological mechanisms that underlie pain-alcohol interactions, with a focus on circuit and molecular mediators of alcohol-induced changes in pain-related behavior. This review briefly discusses some examples of work being done in this area, with a focus on reciprocal projections between the midbrain and extended amygdala, as well as some neurochemical mediators of pain-related phenotypes after alcohol exposure. Finally, as more work accumulates on this topic, the authors highlight the need for the neuroscience field to carefully consider sex and age in the design and analysis of pain-alcohol interaction experiments.


Assuntos
Alcoolismo , Hiperalgesia , Alcoolismo/complicações , Tonsila do Cerebelo , Humanos , Hiperalgesia/induzido quimicamente , Mesencéfalo , Peptídeos
13.
Braz J Med Biol Res ; 54(12): e11071, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34730678

RESUMO

Kahweol is a compound derived from coffee with reported antinociceptive effects. Based on the few reports that exist in the literature regarding the mechanisms involved in kahweol-induced peripheral antinociceptive action, this study proposed to investigate the contribution of the endocannabinoid system to the peripheral antinociception induced in rats by kahweol. Hyperalgesia was induced by intraplantar injection of prostaglandin E2(PGE2) and was measured with the paw pressure test. Kahweol and the drugs to test the cannabinoid system were administered locally into the right hind paw. The endocannabinoids were purified by open-bed chromatography on silica and measured by LC-MS. Kahweol (80 µg/paw) induced peripheral antinociception against PGE2-induced hyperalgesia. This effect was reversed by the intraplantar injection of the CB1 cannabinoid receptor antagonist AM251 (20, 40, and 80 µg/paw), but not by the CB2 cannabinoid receptor antagonist AM630 (100 µg/paw). Treatment with the endocannabinoid reuptake inhibitor VDM11 (2.5 µg/paw) intensified the peripheral antinociceptive effect induced by low-dose kahweol (40 µg/paw). The monoacylglycerol lipase (MAGL) inhibitor, JZL184 (4 µg/paw), and the dual MAGL/fatty acid amide hydrolase (FAAH) inhibitor, MAFP (0.5 µg/paw), potentiated the peripheral antinociceptive effect of low-dose kahweol. Furthermore, kahweol increased the levels of the endocannabinoid anandamide, but not of the other endocannabinoid 2-arachidonoylglycerol nor of anandamide-related N-acylethanolamines, in the plantar surface of the rat paw. Our results suggested that kahweol induced peripheral antinociception via anandamide release and activation of CB1 cannabinoid receptors and this compound could be used to develop new drugs for pain relief.


Assuntos
Diterpenos , Endocanabinoides , Analgésicos/farmacologia , Animais , Café , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Ratos , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide
14.
Eur J Anaesthesiol ; 38(12): 1230-1241, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34735395

RESUMO

BACKGROUND: Remifentanil is an effective drug in peri-operative pain therapy, but it can also induce and aggravate hyperalgesia. Supplemental administration of N2O may help to reduce remifentanil-induced hyperalgesia. OBJECTIVE: To evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion. DESIGN: Single site, phase 1, double-blind, placebo-controlled, randomised crossover study. SETTING: University Hospital, Germany from January 2012 to April 2012. PARTICIPANTS: Twenty-one healthy male volunteers. INTERVENTIONS: Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions in a randomised order: 50 to 50% N2-O2 and intravenous (i.v.) 0.9% saline infusion (placebo); 50 to 50% N2-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (remifentanil); 35 to 15 to 50% N2O-N2-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (tested drug) and 50 to 50% N2O-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (gas active control). Gas mixtures were inhaled for 60 min; i.v. drugs were administered for 30 min. MAIN OUTCOME MEASURES: Areas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min. RESULTS: Data from 20 volunteers were analysed. There were significant treatment and treatment-by-time effects regarding areas of hyperalgesia (P < 0.001). After the treatment period, the area of hyperalgesia was significantly reduced (P < 0.001) in the tested drug and in the gas active control (30.6 ±â€Š9.25 and 24.4 ±â€Š7.3 cm2, respectively) compared with remifentanil (51.0 ±â€Š17.0 cm2). There was also a significant difference between the gas active control and the tested drug sessions (P < 0.001). For the area of allodynia and pain rating, results were consistent with the results for hyperalgesia. CONCLUSIONS: Administration of 35% N2O significantly reduced hyperalgesia, allodynia and pain intensity induced after remifentanil. It might therefore be suitable in peri-operative pain relief characterised by hyperalgesia and allodynia, such as postoperative pain, and may help to reduce opioid demand. TRIAL REGISTRATION: EudraCT-No.: 2011-000966-37.


Assuntos
Óxido Nitroso , Piperidinas , Analgésicos Opioides , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/diagnóstico , Hiperalgesia/tratamento farmacológico , Masculino , Dor Pós-Operatória , Piperidinas/efeitos adversos , Remifentanil
15.
Eur J Neurosci ; 54(10): 7409-7421, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34618385

RESUMO

The activation of spinal astrocytes and release of neuroinflammatory mediators are important events in neuropathic pain (NP) pathogenesis. In this study, we investigated the role of Wnt10a/ß-catenin signalling in kindlin-1-mediated astrocyte activation using a chronic constriction injury (CCI) NP rat model. Using kindlin-1 overexpression and knockdown plasmids, we assessed hyperalgesia, changes in spinal astrocyte activation and the release of inflammatory mediators in a NP rat model. We also performed coimmunoprecipitation, Western blotting and real-time polymerase chain reaction (PCR) to characterize the underlying mechanisms of kindlin-1 in astrocyte cultures in vitro. Kindlin-1 was significantly upregulated in CCI rats and promoted hyperalgesia. Moreover, we observed increased kindlin-1, Wnt10a and glial fibrillary acidic protein (GFAP; biomarker for astroglial injury) levels and the release of inflammatory mediators in NP rats (p < 0.05). Inhibiting GFAP in vitro led to decreased kindlin-1 levels, prevented astrocyte activation, decreased Wnt10a level and the release of inflammatory mediators (p < 0.05). Coimmunoprecipitation showed that kindlin-1 can interact with Wnt10a. We showed that kindlin-1-mediated astrocyte activation was associated with Wnt10a/ß-catenin signalling and the downstream release of inflammatory mediators in a CCI NP rat model. Our findings provide novel insights into the molecular mechanisms of kindlin-1-mediated astrocyte activation after CCI.


Assuntos
Astrócitos , Neuralgia , Animais , Hiperalgesia , Ratos , Ratos Sprague-Dawley , Proteínas Wnt , beta Catenina
16.
ACS Chem Neurosci ; 12(20): 3855-3863, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34610235

RESUMO

Local tissue ischemic hypoxia is a peripheral process that can be targeted with topical treatment to alleviate pain under chronic pain conditions such as complex regional pain syndrome (CRPS) and peripheral neuropathic pain. We recently reported three novel salts and a co-crystal composed of vasoactive agents and antioxidant nutraceuticals, all of which produced potent topical anti-allodynic effects in the chronic postischemic pain (CPIP) rat model of CRPS. One of the products, pentx-pca, is a co-crystal synthesized from pentoxifylline (pentx) and protocatechuic acid (pca). Pentx-pca exhibited potent topical anti-allodynic effects in CPIP and rats with chronic constriction injury of the sciatic nerve exceeding effects produced individually by pentx and pca. We hypothesized that the anti-allodynic effects of pentx-pca in CPIP rats were due to its impact on local tissue oxygenation and subsequent oxygen-dependent mitochondrial respiration. Percutaneous tissue oxygen saturation (SaO2) measurements taken from the hind paw of the CPIP rats revealed that anti-allodynic doses of topical pentx-pca increased local tissue SaO2. Moreover, assessment of the oxygen-dependent mitochondrial function using a triphenyl tetrazolium chloride assay revealed that mitochondrial dysfunction significantly declined in the plantar muscle collected from CPIP rats topically treated with anti-allodynic doses of pentx-pca as compared to vehicle-treated CPIP rats. Furthermore, time-dependent resolution of plantar muscle mitochondrial dysfunction, that occurred in the CPIP rats at 6-week post procedure, paralleled the loss of the anti-allodynic response to topical treatment with pentx-pca. Our results indicated that pentx-pca produced potent anti-allodynic effects in the CPIP rat model of CRPS by alleviating peripheral tissue ischemia/hypoxia and downstream hypoxia-driven mitochondrial dysfunction.


Assuntos
Síndromes da Dor Regional Complexa , Neuralgia , Pentoxifilina , Animais , Modelos Animais de Doenças , Hidroxibenzoatos , Hiperalgesia/tratamento farmacológico , Hipóxia , Neuralgia/tratamento farmacológico , Pentoxifilina/farmacologia , Ratos
17.
J Vis Exp ; (175)2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34661570

RESUMO

Scalding water is the most common cause of burn injury in both elderly and young populations. It is one of the major clinical challenges because of the high mortality and sequelae in low- and middle-income countries. Burns frequently induce intense spontaneous pain and persistent allodynia as well as life-threatening problem. More importantly, excessive pain is often accompanied by depression, which may significantly decrease the quality of life. This article shows how to develop an animal model for the study of burn-induced pain and depression-like behavior. After anesthesia, burn injury was induced by dipping one hind paw of the mouse into hot water (65 °C ± 0.5 °C) for 3 s. The von Frey test and automated gait analysis were performed every 2 days after burn injury. In addition, depression-like behavior was examined using the forced swimming test, and the rota-rod test was performed to differentiate the abnormal motor function after burn injury. The main purpose of this study is to describe the development of an animal model for the study of burn injury-induced pain and depression-like behavior in mice.


Assuntos
Queimaduras , Qualidade de Vida , Animais , Depressão/etiologia , Hiperalgesia , Camundongos , Dor/etiologia
18.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638592

RESUMO

The development of neuropathy and of mood alterations is frequent after chemotherapy. These complications, independent from the antitumoral mechanism, are interconnected due to an overlapping in their processing pathways and a common neuroinflammatory condition. This study aims to verify whether in mice the treatment with the proteasome inhibitor bortezomib (BTZ), at a protocol capable of inducing painful neuropathy, is associated with anxiety, depression and supraspinal neuroinflammation. We also verify if the therapeutic treatment with the antagonist of the prokineticin (PK) system PC1, which is known to contrast pain and neuroinflammation, can prevent mood alterations. Mice were treated with BTZ (0.4 mg/kg three times/week for 4 weeks); mechanical allodynia and locomotor activity were evaluated over time while anxiety (dark light and marble burying test), depression (sucrose preference and swimming test) and supraspinal neuroinflammation were checked at the end of the protocol. BTZ treated neuropathic mice develop anxiety and depression. The presence of mood alterations is related to the presence of neuroinflammation and PK system activation in prefrontal cortex, hippocampus and hypothalamus with high levels of PK2 and PKR2 receptor, IL-6 and TNF-α, TLR4 and an upregulation of glial markers. PC1 treatment, counteracting pain, prevented the development of supraspinal inflammation and depression-like behavior in BTZ mice.


Assuntos
Afeto/efeitos dos fármacos , Bortezomib/farmacologia , Inibidores de Proteassoma/farmacologia , Fator de Crescimento do Endotélio Vascular Derivado de Glândula Endócrina/metabolismo , Animais , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Biomarcadores/metabolismo , Citocinas/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor/tratamento farmacológico , Dor/metabolismo , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Int J Mol Sci ; 22(19)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34638704

RESUMO

The microtubule, a major constituent of cytoskeletons, was shown to bind and interact with transient receptor potential vanilloid subfamily member 1 (TRPV1), and serves a pivotal role to produce thermal hyperalgesia in inflammatory pain. Nogo-A is a modulator of microtubule assembly and plays a key role in maintaining the function of TRPV1 in inflammatory heat pain. However, whether the microtubule dynamics modulated by Nogo-A in dorsal root ganglion (DRG) neurons participate in the inflammatory pain is not elucidated. Here we reported that the polymerization of microtubules in the DRG neurons, as indicated by the acetylated α-tubulin, tubulin polymerization-promoting protein 3 (TPPP3), and microtubule numbers, was significantly elevated in the complete Freund's adjuvant (CFA) induced inflammatory pain. Consistent with our previous results, knock-out (KO) of Nogo-A protein significantly attenuated the heat hyperalgesia 72 h after CFA injection and decreased the microtubule polymerization via up-regulation of phosphorylation of collapsin response mediator protein 2 (CRMP2) in DRG. The colocalization of acetylated α-tubulin and TRPV1 in DRG neurons was also reduced dramatically in Nogo-A KO rats under inflammatory pain. Moreover, the down-regulation of TRPV1 in DRG of Nogo-A KO rats after injection of CFA was reversed by intrathecal injection of paclitaxel, a microtubule stabilizer. Furthermore, intrathecal injection of nocodazole (a microtubule disruptor) attenuated significantly the CFA-induced inflammatory heat hyperalgesia and the mechanical pain in a rat model of spared nerve injury (SNI). In these SNI cases, the Nogo-A and acetylated α-tubulin in DRG were also significantly up-regulated. We conclude that the polymerization of microtubules promoted by Nogo-A in DRG contributes to the development of inflammatory heat hyperalgesia mediated by TRPV1.


Assuntos
Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Neurônios/metabolismo , Proteínas Nogo/metabolismo , Dor/metabolismo , Animais , Técnicas de Silenciamento de Genes , Hiperalgesia/genética , Inflamação/genética , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nogo/genética , Dor/genética , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
20.
Sci Rep ; 11(1): 17971, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504248

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease associated with advanced joint dysfunction. Madhuca indica J. F. Gmel, from the family Sapotaceae, is an Indian medicinal plant reported to have an array of pharmacological properties. The aim of present investigation was to determine the anti-arthritic potential of an isolated phytoconstituent from methanolic leaf extract of Madhuca indica (MI-ALC) against FCA-induced experimental arthritis. Polyarthritis was induced in female rats (strain: Wistar) via an intradermal injection of FCA (0.1 mL) into the tail. Polyarthritis developed after 32 days of FCA administration. Then rats were treated orally with an isolated phytoconstituent from MI-ALC at doses of 5, 10, and 20 mg/kg. Findings suggested that High-Performance Thin-Layer Chromatography, Fourier-Transform Infrared Spectroscopy, and Liquid Chromatography-Mass Spectrometry spectral analyses of the phytoconstituent isolated from MI-ALC confirmed the structure as 3,5,7,3',4'-Pentahydroxy flavone (i.e., QTN). Treatment with QTN (10 and 20 mg/kg) showed significant (p < 0.05) inhibition of increased joint diameter, paw volume, paw withdrawal threshold, and latency. The elevated synovial oxidative stress (Superoxide dismutase, reduced glutathione, and malondialdehyde) and protein levels of Tumor necrosis factor-α (TNF-α) and Interleukin (ILs) were markedly (p < 0.05) reduced by QTN. It also effectively (p < 0.05) ameliorated cyclooxygenase-2 (COX-2), Nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kß) and its inhibitor-α (Ikßα), and ATP-activated P2 purinergic receptors (P2X7) protein expressions as determined by western blot analysis. In conclusion, QTN ameliorates FCA-induced hyperalgesia through modulation of elevated inflammatory release (NF-kß, Ikßα, P2X7, and COX-2), oxido-nitrosative stress, and pro-inflammatory cytokines (ILs and TNF-α) in experimental rats.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Flavonoides/administração & dosagem , Madhuca/química , Fitoterapia/métodos , Extratos Vegetais/administração & dosagem , Plantas Medicinais/química , Adjuvantes Imunológicos/efeitos adversos , Administração Oral , Animais , Antirreumáticos/química , Antirreumáticos/isolamento & purificação , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Feminino , Flavonoides/química , Flavonoides/isolamento & purificação , Adjuvante de Freund/efeitos adversos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Estrutura Molecular , NF-kappa B/metabolismo , Estresse Nitrosativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
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