RESUMO
Complex regional pain syndrome type I (CRPS-I) is a disabling pain condition without adequate treatment. Chronic post-ischemia pain injury (CPIP) is a model of CRPS-I that causes allodynia, spontaneous pain, inflammation, vascular injury, and oxidative stress formation. Antioxidants, such as alpha lipoic acid (ALA), have shown a therapeutic potential for CRPS-I pain control. Thus, we aim to evaluate if ALA repeated treatment modulates neuroinflammation in a model of CRPS-I in mice. We used male C57BL/6 mice to induce the CPIP model (O-ring torniquet for 2 h in the hindlimb). For the treatment with ALA or vehicle (Veh) mice were randomly separated in four groups and received 100 mg/kg orally once daily for 15 days (CPIP-ALA, CPIP-Veh, Control-ALA, and Control-Veh). We evaluated different behavioral tests including von Frey (mechanical stimulus), acetone (cold thermal stimulus), rotarod, open field, hind paw edema determination, and nest-building (spontaneous pain behavior). Also, hydrogen peroxide (H2O2) levels, NADPH oxidase and superoxide dismutase (SOD) activity in the sciatic nerve and spinal cord, and Iba1, Nrf2, and Gfap in spinal cord were evaluated at 16 days after CPIP or sham induction. Repeated ALA treatment reduced CPIP-induced mechanical and cold allodynia and restored nest-building capacity without causing locomotor or body weight alteration. ALA treatment reduced SOD and NADPH oxidase activity, and H2O2 production in the spinal cord and sciatic nerve. CPIP-induced neuroinflammation in the spinal cord was associated with astrocyte activation and elevated Nfr2, which were reduced by ALA. ALA repeated treatment prevents nociception by reducing oxidative stress and neuroinflammation in a model of CRPS-I in mice.
Assuntos
Dor Crônica , Distrofia Simpática Reflexa , Ácido Tióctico , Camundongos , Masculino , Animais , Hiperalgesia , Ácido Tióctico/farmacologia , Doenças Neuroinflamatórias , Nociceptividade , Peróxido de Hidrogênio , Camundongos Endogâmicos C57BL , Distrofia Simpática Reflexa/tratamento farmacológico , Distrofia Simpática Reflexa/complicações , Estresse Oxidativo , Isquemia , NADPH Oxidases/uso terapêutico , Superóxido Dismutase , Modelos Animais de DoençasRESUMO
BACKGROUND: Musculoskeletal pain is a condition that affects bones, muscles, and tendons and is present in various diseases and/or clinical conditions. This type of pain represents a growing problem with enormous socioeconomic impacts, highlighting the importance of developing treatments tailored to the patient's needs. TRP is a large family of non-selective cation channels involved in pain perception. Vanilloid (TRPV1 and TRPV4), ankyrin (TRPA1), and melastatin (TRPM8) are involved in physiological functions, including nociception, mediation of neuropeptide release, heat/cold sensing, and mechanical sensation. OBJECTIVE: In this context, we provide an updated view of the most studied preclinical models of muscle hyperalgesia and the role of transient receptor potential (TRP) in these models. METHODS: This review describes preclinical models of muscle hyperalgesia induced by intramuscular administration of algogenic substances and/or induction of muscle damage by physical exercise in the masseter, gastrocnemius, and tibial muscles. RESULTS: The participation of TRPV1, TRPA1, and TRPV4 in different models of musculoskeletal pain was evaluated using pharmacological and genetic tools. All the studies detected the antinociceptive effect of respective antagonists or reduced nociception in knockout mice. CONCLUSION: Hence, TRPV1, TRPV4, and TRPA1 blockers could potentially be utilized in the future for inducing analgesia in muscle hypersensitivity pathologies.
Assuntos
Dor Musculoesquelética , Canais de Potencial de Receptor Transitório , Camundongos , Animais , Humanos , Canais de Cátion TRPV , Hiperalgesia/tratamento farmacológico , Hiperalgesia/induzido quimicamente , Dor Musculoesquelética/tratamento farmacológico , Canal de Cátion TRPA1 , Manejo da DorRESUMO
Musculoskeletal pain is a widely experienced public healthcare issue, especially after traumatic muscle injury. Besides, it is a common cause of disability, but this pain remains poorly managed. However, the pathophysiology of traumatic muscle injury-associated pain and inflammation has not been fully elucidated. In this regard, the transient receptor potential ankyrin 1 (TRPA1) has been studied in inflammatory and painful conditions. Thus, this study aimed to evaluate the antinociceptive and anti-inflammatory effect of the topical application of a TRPA1 antagonist in a model of traumatic muscle injury in rats. The mechanical trauma model was developed by a single blunt trauma impact on the right gastrocnemius muscle of Wistar male rats (250-350 g). The animals were divided into four groups (Sham/Vehicle; Sham/HC-030031 0.05%; Injury/Vehicle, and Injury/HC-030031 0.05%) and topically treated with a Lanette® N cream base containing a TRPA1 antagonist (HC-030031, 0.05%; 200 mg/muscle) or vehicle (Lanette® N cream base; 200 mg/muscle), which was applied at 2, 6, 12, 24, and 46 h after muscle injury. Furthermore, we evaluated the contribution of the TRPA1 channel on nociceptive, inflammatory, and oxidative parameters. The topical application of TRPA1 antagonist reduced biomarkers of muscle injury (lactate/glucose ratio), spontaneous nociception (rat grimace scale), inflammatory (inflammatory cell infiltration, cytokine levels, myeloperoxidase, and N-acetyl-ß-D-glucosaminidase activities) and oxidative (nitrite levels and dichlorofluorescein fluorescence) parameters, and mRNA Trpa1 levels in the muscle tissue. Thus, these results demonstrate that TRPA1 may be a promising anti-inflammatory and antinociceptive target in treating muscle pain after traumatic muscle injury.
Assuntos
Inflamação , Nociceptividade , Ratos , Masculino , Animais , Ratos Wistar , Canal de Cátion TRPA1 , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Analgésicos/farmacologia , MúsculosRESUMO
AIMS: This article aims to analyze the baseline distribution of TRPA1, TRPV1, TRPV4, and TRPM8 channels in human systems at the transcriptional level. MAIN METHODS: Using the RNA-seq dataset from the National Center for Biotechnology Information (NCBI) gene database, we investigated and compared the transcriptional levels of TRPV1, TRPA1, TRPV4 and TRPM8 found in 95 human subjects representing 33 different tissues to determine the tissue specificity of all protein-coding genes. KEY FINDING: In this study, we observed higher transcriptional levels for TRPV1 (duodenum), TRPA1 (Urinary bladder), TRPV4 (Kidney) and TRPM8 (Prostate) compared to the other TRPs. SIGNIFICANCE: These channels are involved in developing inflammatory and painful pathologies and seem to participate in cancer development. This information on transcriptional levels of TRPV1, TRPA1, TRPV4 and TRPM8 in human systems may provide essential suggestions for further studies on these proteins.
Assuntos
Canais de Cátion TRPM , Canais de Potencial de Receptor Transitório , Humanos , Masculino , Proteínas de Membrana/metabolismo , Canal de Cátion TRPA1/genética , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Canais de Potencial de Receptor Transitório/genéticaRESUMO
Multiple sclerosis (MS) is a chronic neurodegenerative and autoimmune disease. Motor, sensory and cognitive deficits in MS are commonly accompanied by psychiatric disorders. Depression and anxiety affect the quality of life of MS patients, and the treatment is still not well-established. Prevalence rates in MS patients for depression and anxiety vary widely between studies. However, the prevalence of these psychiatric disorders in the subgroups of MS patients and their association with a disability has not been studied yet. Therefore, this systematic review and meta-analysis proposes to estimate the prevalence of depression and anxiety in MS and to perform subgroup analyses (study type, Extended Disability Status Scale/EDSS, duration of MS, region, type of MS) on observational studies. The protocol was registered in PROSPERO (4202125033). A computerized search on PubMed, EMBASE and Scopus for studies on depression and anxiety in MS was performed from 2015 to 2021, and 12 articles were included. Most of the studies in the meta-analysis had a low risk of bias. The prevalence of depression was 27.01% (MS), 15.78% (relapsing-remitting multiple sclerosis/RRMS), and 19.13% (progressive multiple sclerosis/PMS). For anxiety the prevalence was 35.19% (MS), 21.40% (RRMS), and 24.07% (PMS). The prevalence of depression/anxiety for patients with EDSS <3 was 26.69/45.56% and for EDSS >3 was 22.96/26.70%. Using HADS-A (8) the prevalence was 38.5% and for depression was 22.4%. Then, our study brought together current data regarding psychiatric disorders in MS patients, which are comorbidities that affect the quality of life of these patients.
RESUMO
Headaches are frequently described in progressive multiple sclerosis (PMS) patients, but their mechanism remains unknown. Transient receptor potential ankyrin 1 (TRPA1) was involved in neuropathic nociception in a model of PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE), and TRPA1 activation causes periorbital and facial nociception. Thus, our purpose was to observe the development of periorbital mechanical allodynia (PMA) in a PMS-EAE model and evaluate the role of TRPA1 in periorbital nociception. Female PMS-EAE mice elicited PMA from day 7 to 14 days after induction. The antimigraine agents olcegepant and sumatriptan were able to reduce PMA. The PMA was diminished by the TRPA1 antagonists HC-030031, A-967079, metamizole and propyphenazone and was absent in TRPA1-deficient mice. Enhanced levels of TRPA1 endogenous agonists and NADPH oxidase activity were detected in the trigeminal ganglion of PMS-EAE mice. The administration of the anti-oxidants apocynin (an NADPH oxidase inhibitor) or alpha-lipoic acid (a sequestrant of reactive oxygen species), resulted in PMA reduction. These results suggest that generation of TRPA1 endogenous agonists in the PMS-EAE mouse model may sensitise TRPA1 in trigeminal nociceptors to elicit PMA. Thus, this ion channel could be a potential therapeutic target for the treatment of headache in PMS patients.
RESUMO
Progressive multiple sclerosis (PMS) is a neurological disease associated with the development of depression and anxiety, but treatments available are unsatisfactory. The transient receptor potential ankyrin 1 (TRPA1) is a cationic channel activated by reactive compounds, and the blockage of this receptor can reduce depression- and anxiety-like behaviors in naive mice. Thus, we investigated the role of TRPA1 in depression- and anxiety-like behaviors in a PMS model in mice. PMS model was induced in C57BL/6 female mice by the experimental autoimmune encephalomyelitis (EAE). Nine days after the PMS-EAE induction, behavioral tests (tail suspension and elevated plus maze tests) were performed to verify the effects of sertraline (positive control), selective TRPA1 antagonist (A-967,079), and antioxidants (α-lipoic acid and apocynin). The prefrontal cortex and hippocampus were collected to evaluate biochemical and inflammatory markers. PMS-EAE induction did not cause locomotor changes but triggered depression- and anxiety-like behaviors, which were reversed by sertraline, A-967,079, α-lipoic acid, or apocynin treatments. The neuroinflammatory markers (AIF1, GFAP, IL-1ß, IL-17, and TNF-α) were increased in mice's hippocampus. Moreover, this model did not alter TRPA1 RNA expression levels in the hippocampus but decrease TRPA1 levels in the prefrontal cortex. Moreover, PMS-EAE induced an increase in NADPH oxidase and superoxide dismutase activities and TRPA1 endogenous agonist levels (hydrogen peroxide and 4-hydroxynonenal). TRPA1 plays a fundamental role in depression- and anxiety-like behaviors in a PMS-EAE model; thus, it could be a possible pharmacological target for treating these symptoms in PMS.
Assuntos
Ansiedade/genética , Ansiedade/psicologia , Comportamento Animal , Depressão/genética , Depressão/psicologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/psicologia , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Crônica Progressiva/psicologia , Canal de Cátion TRPA1/genética , Animais , Antioxidantes/farmacologia , Feminino , Elevação dos Membros Posteriores , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Oximas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sertralina/farmacologia , Canal de Cátion TRPA1/antagonistas & inibidoresRESUMO
Muscle pain is the most prevalent type of pain in the world, but treatment remains ineffective. Thus, it is relevant to develop trustable animal models to understand the involved pain mechanisms. Therefore, this study characterised the nociception and inflammation in a traumatic muscle injury model in rats. A single blunt trauma impact on the right gastrocnemius muscle of male Wistar rats (250-350 g) was used as model for muscle pain. Animals were divided into four groups (sham/no treatment; sham/diclofenac 1%; injury/no treatment; injury/diclofenac 1%) and the topical treatment with a cream containing 1% monosodium diclofenac (applied at 2, 6, 12, 24, and 46 h after muscle injury; 200 mg/muscle) was used as an anti-inflammatory control. Nociception (mechanical and cold allodynia, or nociceptive score) and locomotor activity were evaluated at 26 and 48 h after injury. Also, inflammatory and oxidative parameters were evaluated in gastrocnemius muscle and the creatine kinase (CK) activity and lactate/glicose levels in rat's serum and plasma, respectively. Muscle injury caused mechanical and cold allodynia, and increased nociceptive scores, without inducing locomotor impairment. This model also increased the inflammatory cells infiltration (seen by myeloperoxidase and N-acetyl-ß-D-glucosaminidase activities and histological procedure), nitric oxide, interleukin (IL)-1ß, IL-6, and dichlorofluorescein fluorescence in muscle samples; and CK activity and lactate/glicose ratio. The treatment with 1% monosodium diclofenac reduced inflammatory cells infiltration, dichlorofluorescein fluorescence and lactate/glicose levels. Thus, we characterised the traumatic muscle injury as a reproducible model of muscle pain, which makes it possible to evaluate promising antinociceptive and anti-inflammatory therapies.
Assuntos
Inflamação , Dor Musculoesquelética , Nociceptividade , Dor Nociceptiva , Ferimentos não Penetrantes , Administração Tópica , Analgésicos/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Comportamento Animal , Citocinas/metabolismo , Diclofenaco/administração & dosagem , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/fisiopatologia , Mediadores da Inflamação/metabolismo , Locomoção , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/lesões , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Dor Musculoesquelética/tratamento farmacológico , Dor Musculoesquelética/metabolismo , Dor Musculoesquelética/fisiopatologia , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/tratamento farmacológico , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Estresse Oxidativo , Ratos Wistar , Ferimentos não Penetrantes/tratamento farmacológico , Ferimentos não Penetrantes/metabolismo , Ferimentos não Penetrantes/fisiopatologiaRESUMO
Arachis hypogaea L. (peanut) leaf is traditionally used for the treatment of insomnia in Asia. However, studies describing the safety and toxicity profile for this plant preparation are limited. Thus, the goal of this study was to investigate the toxicity of peanut leaf hydroalcoholic extract (PLHE) repeated treatment. The extract was administered orally (100, 300 or 1000 mg/kg) in male and female Wistar rats for 28 days (OECD guideline 407). PLHE treatment did not cause mortality or weight variation in the animals. Also, there was no alteration on locomotor activity (open field test), motor coordination (rotarod test), or anxiety behaviour (elevated plus-maze test). Male rats had a reduction in relative liver weight (100 mg/kg) and an increase in total kidney weight (1000 mg/kg), but there was no change in biochemical and haematological parameters after PLHE treatment. Free extracellular double-stranded DNA (dsDNA) levels was also evaluated, but PLHE treatment did not increase this parameter in rat organs. Also, the dose of 1000 mg/kg of PLHE significantly increased the total thiols in the liver of females compared with the control animals. Thus, PLHE did not induce toxicity after repeated exposure for 28 days in rats.
Assuntos
Arachis , Extratos Vegetais/toxicidade , Administração Oral , Álcoois/química , Animais , Feminino , Masculino , Folhas de Planta , Ratos Wistar , Solventes/química , Testes de Toxicidade SubagudaRESUMO
Central neuropathic pain is a common untreated symptom in progressive multiple sclerosis (PMS) and is associated with poor quality of life and interference with patients' daily activities. The neuroinflammation process and mitochondrial dysfunction in the PMS lesions generate reactive species. The transient potential receptor ankyrin 1 (TRPA1) has been identified as one of the major mechanisms that contribute to neuropathic pain signaling and can be activated by reactive compounds. Thus, the goal of our study was to evaluate the role of spinal TRPA1 in the central neuropathic pain observed in a PMS model in mice. We used C57BL/6 female mice (20-30 g), and the PMS model was induced by the experimental autoimmune encephalomyelitis (EAE) using mouse myelin oligodendrocyte glycoprotein (MOG35-55) antigen and CFA (complete Freund's adjuvant). Mice developed progressive clinical score, with motor impairment observed after 15 days of induction. This model induced mechanical and cold allodynia and heat hyperalgesia which were measured up to 14 days after induction. The hypersensitivity observed was reduced by the administration of selective TRPA1 antagonists (HC-030031 and A-967079, via intrathecal and intragastric), antioxidants (α-lipoic acid and apocynin, via intrathecal and intragastric), and TRPA1 antisense oligonucleotide (via intrathecal). We also observed an increase in TRPA1 mRNA levels, NADPH oxidase activity, and 4-hydroxinonenal (a TRPA1 agonist) levels in spinal cord samples of PMS-EAE induced animals. In conclusion, these results support the hypothesis of the TRPA1 receptor involvement in nociception observed in a PMS-EAE model in mice.