RESUMO
Chronic neuropathic pain (CNP) is a vast world health problem often associated with the somatosensory domain. This conceptualization is problematic because, unlike most other sensations that are usually affectively neutral and may present emotional, affective, and cognitive impairments. Neuronal circuits that modulate pain can increase or decrease painful sensitivity based on several factors, including context and expectation. The objective of this study was to evaluate whether subchronic treatment with Cannabidiol (CBD; 0.3, 3, and 10 mg/kg intraperitoneal route - i.p., once a day for 3 days) could promote pain-conditioned reversal, in the conditioned place preference (CPP) test, in male Wistar rats submitted to chronic constriction injury (CCI) of the sciatic nerve. Then, we evaluated the expression of astrocytes and microglia in animals treated with CBD through the immunofluorescence technique. Our results demonstrated that CBD promoted the reversal of CPP at 3 and 10 mg/kg. In CCI animals, CBD was able to attenuate the increase in neuronal hyperactivity, measured by FosB protein expression, in the regions of the corticolimbic circuit: anterior cingulate cortex (ACC), complex basolateral amygdala (BLA), granular layer of the dentate gyrus (GrDG), and dorsal hippocampus (DH) - adjacent to subiculum (CA1). CBD also prevented the increased expression of GFAP and IBA-1 in CCI animals. We concluded that CBD effects on CNP are linked to the modulation of the aversive component of pain. These effects decrease chronic neuronal activation and inflammatory markers in regions of the corticolimbic circuit.
Assuntos
Canabidiol , Neuralgia , Ratos , Animais , Masculino , Ratos Wistar , Canabidiol/farmacologia , Aprendizagem da Esquiva , Doenças Neuroinflamatórias , Neuralgia/tratamento farmacológico , Neuralgia/metabolismoRESUMO
Background: Temporomandibular joint (TMJ)-associated inflammation contributes to the pain reported by patients with temporomandibular disorders (TMD). It is common for patients diagnosed with TMD to report pain in the masticatory muscles and temporomandibular joints, headache, and jaw movement disturbances. Although TMD can have different origins, including trauma and malocclusion disorder, anxiety/depression substantially impacts the development and maintenance of TMD. In general, rodent studies on orofacial pain mechanisms involve the use of tests originally developed for other body regions, which were adapted to the orofacial area. To overcome limitations and expand knowledge in orofacial pain, our group validated and characterized an operant assessment paradigm in rats with both hot and cold stimuli as well mechanical stimuli. Nevertheless, persistent inflammation of the TMJ has not been evaluated with this operant orofacial pain assessment device (OPAD). Methods: We characterized the thermal orofacial sensitivity for cold, neutral, and hot stimuli during the development of TMD using the OPAD behavior test. In addition, we evaluated the role of transient receptor potential vanilloid 1 (TRPV1) expressing nociceptors in rats with persistent TMJ inflammation. The experiments were performed in male and female rats with TMJ inflammation induced by carrageenan (CARR). Additionally, resiniferatoxin (RTX) was administered into the TMJs prior CARR to lesion TRPV1-expressing neurons to evaluate the role of TRPV1-expressing neurons. Results: We evidenced an increase in the number of facial contacts and changes in the number of reward licks per stimulus on neutral (37°C) and cold (21°C) temperatures. However, at the hot temperature (42°C), the inflammation did not induce changes in the OPAD test. The prior administration of RTX in the TMJ prevented the allodynia and thermal hyperalgesia induced by CARR. Conclusion: We showed that TRPV-expressing neurons are involved in the sensitivity to carrageenan-induced pain in male and female rats evaluated in the OPAD.
RESUMO
Chronic restraint stress (CRS) can have different behavioral effects depending on variables associated with the stressor and the organism. This study aimed to verify the effect of the interaction between sex and duration of the CRS protocol in rats. Sprague-Dawley rats were divided by sex, intervention (CRS; control), and CRS duration (11 days; 22 days). Rats exposed to CRS showed better spatial learning than controls in the Morris water maze test, regardless of sex and stress duration. Males exposed to CRS for 11 days showed a higher rate of behaviors associated with anxiety than males exposed to 22 days of CRS at the elevated plus maze test, but the same was not observed in females. The weight gain of animals exposed to stress decreased in the first 11 days, showing a recovery from day 11 to day 22 of intervention. No effects of CRS were observed on behaviors associated with depression in the sucrose preference test. The results suggest habituation to the protocol, with a progressive decrease in the harmful effects of stress on and maintenance of the beneficial effects. It is possible that females are more resistant to the harmful effects of CRS on anxiety.
Assuntos
Aprendizagem Espacial , Estresse Psicológico , Masculino , Feminino , Ratos , Animais , Ratos Sprague-Dawley , Restrição Física/métodos , Ansiedade , Aprendizagem em LabirintoRESUMO
The activation of heme oxygenase 1 (HO-1)/carbon monoxide (CO) inhibits chronic inflammatory pain, but its role in the central nervous system (CNS) is not entirely known. We evaluated whether the treatment with an HO-1 inducer, cobalt protoporphyrin IX (CoPP), or a CO-releasing molecule, tricarbonyldichlororuthenium(II)dimer (CORM-2), modulates the nociceptive, apoptotic and/or oxidative responses provoked by persistent inflammatory pain in the CNS. In C57BL/6 male mice with peripheral inflammation caused by complete Freund's adjuvant (CFA), we assessed the effects of CORM-2 and CoPP on the expression of protein kinase B (Akt), the apoptotic protein BAX, and the antioxidant enzymes HO-1 and NADPH quinone oxidoreductase 1 (NQO1) in the periaqueductal gray matter (PAG), amygdala (AMG), ventral hippocampus (VHPC) and medial septal area (MSA). Our results showed that the increased expression of p-Akt caused by peripheral inflammation in the four analyzed brain areas was reversed by CORM-2 and CoPP therapies. Both treatments also normalized the upregulation of BAX induced by CFA on the VHPC and MSA. Oxidative stress, demonstrated with the decreased expression of HO-1 on the PAG and AMG, was normalized in CORM-2 and CoPP treated animals. CoPP also increased the expression of HO-1 on VHPC, and both treatments up-regulated the NQO1 levels on the PAG of CFA-injected animals. In conclusion, both CORM-2 and CoPP treatments inhibited the nociceptive and apoptotic responses generated by peripheral inflammation and/or potentiated the antioxidant responses in several brain areas revealing the new modulatory effects of these treatments in the CNS of animals with chronic inflammatory pain.
Assuntos
Dor Crônica , Compostos Organometálicos , Animais , Antioxidantes/metabolismo , Monóxido de Carbono/metabolismo , Sistema Nervoso Central/metabolismo , Dor Crônica/metabolismo , Heme Oxigenase-1/metabolismo , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptividade , Compostos Organometálicos/metabolismo , Compostos Organometálicos/farmacologia , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
Psychological stress and occlusal alterations are contributing etiologic factors for temporomandibular and muscular disorders in the orofacial area. The neural modulation recruited for this relationship, however, is not elucidated. The aim of this study was to investigate potential central mechanisms involved in the exodontia-induced occlusal instability associated with unpredictable chronic stress (UCS). Male adult Wistar rats were submitted to occlusal instability (unilateral molar teeth extraction) and/or to a UCS protocol and treated with diazepam or vehicle. The anxiety-like behavior was evaluated by elevated plus maze (EPM) and open field (OF) tests. Limbic structures such as the central nucleus of the amygdala (CeA), paraventricular nucleus of the hypothalamus (PVN), dorsal periaqueductal gray matter (dPAG) and nucleus accumbens core (NAc) were analyzed for expression of FosB/ΔFosB (immediate early genes) by immunohistochemistry. Exodontia and/or UCS decreased the time spent in the open arms at the EPM and the distance travelled at the OF, and increased the immobility time at the OF, suggesting anxiety-like behavior. In addition, exodontia induction resulted in an upregulation of FosB/ΔFosB in the CeA, PVN and dPAG, while UCS and exodontia + UCS upregulate FosB/ΔFosB immunoreactivity in the CeA, PVN, dPAG and NAc. Treatment with diazepam decreased the expression of FosB/ΔFosB in all analyzed structures of animals subject to UCS and exodontia + UCS, while promoted a reduction in the FosB/ΔFosB expression in the CeA, PVN and dPAG in animals subject to exodontia. Our findings showed an anxiogenic effect of exodontia and UCS, which is correlated with intranuclear neuron activation of limbic structures in a spatially dependent manner and that is prevented by the administration of diazepam.
Assuntos
Sistema Límbico/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Estresse Psicológico/metabolismo , Extração Dentária , Animais , Ansiolíticos/farmacologia , Diazepam/farmacologia , Imuno-Histoquímica , Sistema Límbico/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Regulação para CimaRESUMO
The incidence of chronic pain is high in the general population and it is closely related to anxiety disorders, which promote negative effects on the quality of life. The cannabinoid system has essential participation in the pain sensitivity circuit. In this perspective, cannabidiol (CBD) is considered a promising strategy for treating neuropathic pain. Our study aimed to evaluate the effects of sub-chronic systemic treatment with CBD (0.3, 3, 10, or 30 mg/kg, i.p.) in male in rats submitted to chronic constriction injury of the sciatic nerve (CCI) or not (SHAM) and assessed in nociceptive tests (von Frey, acetone, and hot plate, three days CBD's treatment) and in the open field test (OFT, two days CBD's treatment). We performed a screening immunoreactivity of CB1 and TRPV1 receptors in cortical and limbic regions tissues, which were collected after 1.5 h of behavioral tests on the 24th experimental day. This study presents a dose-response curve to understand better the effects of low doses (3 mg/kg) on CBD's antiallodynic and anxiolytic effects. Also, low doses of CBD were able to (1) reverse mechanical and thermal allodynia (cold) and hyperalgesia, (2) reverse anxious behaviors (reduction of the % of grooming and freezing time, and increase of the % of center time in the OFT) induced by chronic pain. The peripheral neuropathy promoted the increase in the expression of CB1 and TRPV1 receptors in the anterior cingulate cortex (ACC), anterior insular cortex (AIC), basolateral amygdala (BLA), dorsal hippocampus (DH), and ventral hippocampus (VH). CBD potentiated this effect in the ACC, AIC, BLA, DH, and VH regions. These results provide substantial evidence of the role of the ACC-AIC-BLA corticolimbic circuit, and BLA-VH for pain regulation. These results can be clinically relevant since they contribute to the evidence of CBD's beneficial effects on treating chronic pain and associated comorbidities such as anxiety.
Assuntos
Ansiedade/tratamento farmacológico , Canabidiol/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Receptor CB1 de Canabinoide/efeitos dos fármacos , Canais de Cátion TRPV/efeitos dos fármacos , Animais , Ansiedade/psicologia , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Temperatura Alta , Sistema Límbico/efeitos dos fármacos , Masculino , Rede Nervosa/efeitos dos fármacos , Neuralgia/metabolismo , Neuralgia/psicologia , Medição da Dor/efeitos dos fármacos , Estimulação Física , Ratos , Ratos Wistar , Ciática/tratamento farmacológicoRESUMO
Temporomandibular disorder (TMD) is characterized by acute or chronic orofacial pain, which can be associated with inflammatory processes in the temporomandibular joint (TMJ) and emotional disorders. Peripheral and central sensitization in painful orofacial processes is common, and it can be triggered by peripheral inflammatory challenge with consequent neuroinflammation phenomena. Such neuroinflammation comes from inflammatory products from supportive cells, blood-brain barrier, and extracellular matrix. Here, we evaluated the possible recruitment of limbic structures for modified matrix metalloproteinases (MMPs) expression and activity during temporomandibular inflammation-induced orofacial persistent pain. The inflammatory process in TMJs of rats was induced by Freund's Complete Adjuvant (CFA) administration. The activity and expression of MMPs-2 and 9 were assessed by in situ zymography and conventional zymography, respectively. A glial colocalization with the MMPs was performed using immunofluorescence. The results evidenced both short- and long-term alterations on MMP-2 and -9 expression in the limbic structures following CFA-induced temporomandibular inflammation. The gelatinolytic activity was increased in the central amygdala, hippocampus, hypothalamus, ventrolateral periaqueductal gray (vlPAG), superior colliculus, and inferior colliculus. Finally, an increase of colocalization of MMP-2/GFAP and MMP-9/GFAP in CFA-induced inflammation groups was observed when compared with saline groups in the central amygdala and vlPAG. It is possible to suggest that glial activation is partly responsible for the production of gelatinases in the persistent orofacial pain, and it is involved in the initiation and maintenance of this process, indicating that inhibition of MMPs might be pursued as a potential new therapeutic target for TMD.
Assuntos
Inflamação/patologia , Sistema Límbico/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Transtornos da Articulação Temporomandibular/enzimologia , Transtornos da Articulação Temporomandibular/patologia , Articulação Temporomandibular/enzimologia , Articulação Temporomandibular/patologia , Tonsila do Cerebelo/metabolismo , Animais , Astrócitos/metabolismo , Dor Facial/complicações , Adjuvante de Freund , Gelatina/metabolismo , Gelatinases/metabolismo , Sistema Límbico/patologia , Masculino , Ratos Wistar , Regulação para CimaRESUMO
Carbon monoxide (CO) and nitric oxide (NO) modulate inflammatory nociception and anxiety. We evaluate whether treatments with a heme oxygenase-1 (HO-1) inducer (CoPP) or a carbon monoxide-releasing molecule (CORM-2) are capable of inhibiting inflammatory pain aversiveness in wild type (WT) and inducible nitric oxide synthase-knock out (NOS2-KO) mice with persistent inflammation and its relationship with µ- (MOR) and δ- (DOR) opioid receptors. WT and NOS2-KO male mice with complete Freund's adjuvant (CFA) injected into the hind paw were evaluated in the von Frey and the escape-avoidance paradigm (PEAP) tests, at 10 days, before and after the treatment with CORM-2 (5 mg/kg) or CoPP (2.5 mg/kg). WT mice groups treated with CORM-2 or CoPP also received naloxone (NLX, a non-specific opioid receptor antagonist). The HO-1, neuronal nitric oxide synthase, NOS2, MOR, and DOR expression in the dorsal hippocampus were evaluated by western blot. CFA reduced mechanical threshold in WT and NOS2-KO mice but only increased the percentage of time in the light compartment in the PEAP in WT mice. CORM-2 and CoPP inhibited these effects in both strains. Pre-treatment with NLX reverses the anti-allodynic and anti-aversive effects of CORM-2 or CoPP in WT mice. CORM-2 and CoPP increases the protein levels of HO-1, MOR and DOR in the dorsal hippocampus of WT mice but not in NOS2-KO animals. Results showed that HOCO pathway activation promotes anti-allodynic effects and reduced pain aversiveness caused by peripheral inflammation by increasing the expression of MOR and DOR activated by HO-1 in the dorsal hippocampus.
Assuntos
Monóxido de Carbono/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hipocampo/metabolismo , Nociceptividade/fisiologia , Dor/metabolismo , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Animais , Aprendizagem da Esquiva/fisiologia , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Compostos Organometálicos/farmacologia , Medição da Dor , Pirazinas/farmacologia , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Psychological stress and occlusal alteration are important etiologic factors for temporomandibular/masticatory muscular disorders. In particular, the exact physiologic mechanism underlying the relation by occlusal alteration and temporomandibular disorders remains unclear. Our purpose was to test the hypothesis that benzodiazepine therapy is able to prevent metabolic and vascular changes in the medial pterygoid muscle of rats under chronic stress after 14 days of unilateral exodontia. Adult Wistar rats were submitted to unpredictable chronic mild stress (10 days) and/or unilateral exodontia and their plasma and medial pterygoid muscles were removed for analysis. A pre-treatment with diazepam was used to verify its effect on stress. The parameters evaluated included anxiety behavior, plasma levels of corticosterone, metabolic activity by succinate dehydrogenase, capillary density by laminin staining and ultrastructural findings by transmission electron microscopy. Occlusal instability induced anxiety-like behavior on elevated plus-maze test and diazepam administration blocked the appearance of this behavior. Unilateral exodontia promoted in the contralateral muscle an increase of oxidative fibers and capillaries and modification of sarcoplasmic reticulum. Chronic stress caused increased glycolytic metabolism, reduced capillary density and morphological changes in mitochondria on both sides. Association of both factors induced a glycolytic pattern in muscle and hemodynamic changes. Pharmacological manipulation with diazepam inhibited the changes in the medial pterygoid muscle after stress. Our results reveal a preventive benzodiazepine treatment for stress and occlusal instability conditions affecting masticatory muscle disorders. In addition, provide insights into the mechanisms by which chronic stress and exodontia might be involved in the pathophysiology of masticatory muscular dysfunctions.
Assuntos
Benzodiazepinas/administração & dosagem , Músculos da Mastigação/fisiopatologia , Estresse Psicológico/tratamento farmacológico , Transtornos da Articulação Temporomandibular/tratamento farmacológico , Animais , Benzodiazepinas/farmacologia , Estudos de Casos e Controles , Diazepam/efeitos adversos , Modelos Animais de Doenças , Masculino , Músculos da Mastigação/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Ratos , Ratos Wistar , Estresse Psicológico/induzido quimicamente , Transtornos da Articulação Temporomandibular/fisiopatologia , Extração Dentária , Resultado do TratamentoRESUMO
The mechanisms underlying temporomandibular disorders following orofacial pain remain unclear. Hydrogen sulfide (H2S), a newly identified gasotransmitter, has been reported to modulate inflammation. Cystathionine γ-lyase (CSE) is responsible for the systemical production of H2S, which exerts both pro- and antinociceptive effects through inflammation. In the current study, we investigated whether the endogenous H2S production pathway contributes to arousal and maintenance of orofacial inflammatory pain, through the investigation of the effects of a CSE inhibitor, propargyglycine (PAG), in a rat CFA (Complete Freund Adjuvant)-induced temporomandibular inflammation model to mimic persistent pain in the orofacial region. For this, rats received either CFA or saline in the temporomandibular joints (TMJs), and after 3 or 14 days, they received a single injection of PAG or saline and were evaluated for nociception with the von Frey and formalin test. Also, pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) were analyzed in TMJs and trigeminal ganglion (TG). In this last one, glial cells reactivity was also verified. Endogenous H2S production rate were measured in both, TMJ and TG. Our results indicated decreased allodynia and hyperalgesic responses in rats submitted to CFA after injection of PAG. Moreover, PAG inhibited leucocyte migration to temporomandibular synovial fluid after 3 and 14 days of inflammation. PAG was able to reduce levels of CBS, CSE, TNF-α, and IL-1ß in the TMJ and TG, after 13 days of CFA injection. The observed increased activation of glial cells in the trigeminal ganglia on the 14th day of inflammation can be prevented by the highest dose of PAG. Finally, CBS and CSE expression, and endogenous H2S production rate in the TMJ and TG was found higher in rats with persistent temporomandibular inflammation compared to rats injected with saline and PAG was able to prevent this elevation. Our results elucidated the molecular mechanisms by which H2S exerts its pro-inflammatory and pro-nociceptive role in the orofacial region by alterations in both local tissue and TG.
Assuntos
Alcinos/uso terapêutico , Glicina/análogos & derivados , Sulfeto de Hidrogênio/metabolismo , Hiperalgesia/tratamento farmacológico , Inflamação/metabolismo , Dor/tratamento farmacológico , Articulação Temporomandibular/metabolismo , Animais , Cistationina gama-Liase/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Glicina/uso terapêutico , Interleucina-1beta/metabolismo , Masculino , Neuroglia/efeitos dos fármacos , Ratos Wistar , Gânglio Trigeminal/citologia , Gânglio Trigeminal/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Accurate diagnosis and treatment of pain is dependent on knowledge of the variables that might alter this response. Some of these variables are the locality of the noxious stimulus, the sex of the individual, and the presence of chronic diseases. Among these chronic diseases, hypertension is considered a serious and silent disease that has been associated with hypoalgesia. The main goal of this study was to evaluate the potential nociceptive differences in spontaneously hypertensive rats (SHR) regarding the locality of the stimulus, i.e., the temporomandibular joint or paw, the sex, and the role of ovarian hormones in a model of mechanical nociception (Von Frey test) or formalin-induced inflammatory nociception. Our results indicate that SHR had lower orofacial mechanical nociception beyond the lower mechanical nociception in the paw compared with WKY rats. In a model of formalin-induced inflammatory nociception, SHR also had decreased nociception compared with normotensive rats. We also sought to evaluate the influence of sex and ovarian hormones on orofacial mechanical nociception in SHR. We observed that female SHR had higher mechanical nociception than male SHR only in the paw, but it had higher formalin-induced orofacial nociception than male SHR. Moreover, the absence of ovarian hormones caused an increase in mean arterial pressure and a decrease in paw nociception in female SHR.
Assuntos
Hormônios/farmacologia , Hipertensão/fisiopatologia , Nociceptividade/fisiologia , Caracteres Sexuais , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Feminino , Hormônios/metabolismo , Hipertensão/metabolismo , Masculino , Nociceptividade/efeitos dos fármacos , Ovário , Dor/fisiopatologia , Medição da Dor , Ratos Endogâmicos SHR/metabolismo , Ratos Endogâmicos WKYRESUMO
Objective: Animal models of chronic pain have demonstrated that glial cells are promising target for development of analgesic drugs. However, preclinical studies on glial response under chronic pain conditions vary depending on the cellular markers, the species used, the experimental design and model. Therefore, we investigate the expression profile of GFAP and Iba-1 during the behavioral manifestation of sensory disorder in inflammatory and neuropathic pain models. Methods: the expression profile of fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) were quantitated in the spinal dorsal horn of Balb/C mice submitted to six models of chronic pain. Protein analysis was performed by western blot and the results colligated with pain-related behavior. Results: Using the same method to quantitate proteins we observed that while GFAP is upregulated after axotomy, partial nerve injury and cutaneous inflammation, its expression is not changed during muscle inflammation, non-inflammatory muscle pain, and in a viral-associated pain. Differently, Iba-1 is downregulated after axotomy but upregulated after partial lesion of peripheral nerve as well as after virus inoculation and during non-inflammatory muscle pain. Cutaneous and muscle inflammation induced no change in Iba-1 expression in the dorsal horn.In spite of a marked time-dependent variation in protein expression, mechanical allodynia was present at any time of all the models investigated. Discussion: Under distinct pain conditions, GFAP and Iba-1 expression is dependent on the origin of the stimulus, disease progression and tissue affected. Moreover, their expression and is not necessarily associated to the behavior manifestation of pain.
Assuntos
Proteínas de Ligação ao Cálcio/biossíntese , Dor Crônica/metabolismo , Proteína Glial Fibrilar Ácida/biossíntese , Inflamação/metabolismo , Proteínas dos Microfilamentos/biossíntese , Neuralgia/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Animais , Modelos Animais de Doenças , Regulação para Baixo , Inflamação/complicações , Inflamação/fisiopatologia , Masculino , Camundongos , Músculos/fisiopatologia , Nervo Isquiático/lesões , Pele/fisiopatologia , Regulação para CimaRESUMO
Tonic immobility (TI) is a temporary state of profound motor inhibition associated with great danger as the attack of a predator. Previous studies carried out in our laboratory evidenced high Fos-IR in the posteroventral region of the medial nucleus of the amygdala (MEA) after induction of the TI response. Here, we investigated the effects of GABAA and GABAB of the MEA on TI duration. Intra-MEA injections of the GABAA agonist muscimol and GABAB agonist baclofen reduced TI response, while intra-MEA injections of the GABAA antagonist bicuculline and GABAB antagonist phaclofen increased the TI response. Moreover, the effects observed with muscimol and baclofen administrations into MEA were blocked by pretreatment with bicuculline and phaclofen (at ineffective doses per se). Finally, the activation of GABAA and GABAB receptors in the MEA did not alter the spontaneous motor activity in the open field test. These data support the role of the GABAergic system of the MEA in the modulation of innate fear.
Assuntos
Complexo Nuclear Corticomedial/fisiologia , Agonistas de Receptores de GABA-A/fisiologia , Agonistas dos Receptores de GABA-B/fisiologia , Resposta de Imobilidade Tônica/fisiologia , Animais , Baclofeno/administração & dosagem , Baclofeno/análogos & derivados , Baclofeno/antagonistas & inibidores , Baclofeno/farmacologia , Bicuculina/administração & dosagem , Bicuculina/farmacologia , Complexo Nuclear Corticomedial/efeitos dos fármacos , Agonistas de Receptores de GABA-A/administração & dosagem , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/administração & dosagem , Antagonistas de Receptores de GABA-A/farmacologia , Agonistas dos Receptores de GABA-B/administração & dosagem , Agonistas dos Receptores de GABA-B/farmacologia , Antagonistas de Receptores de GABA-B/administração & dosagem , Antagonistas de Receptores de GABA-B/farmacologia , Cobaias , Resposta de Imobilidade Tônica/efeitos dos fármacos , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Muscimol/administração & dosagem , Muscimol/antagonistas & inibidores , Muscimol/farmacologiaRESUMO
Rocio virus (ROCV) is a highly neuropathogenic mosquito-transmitted flavivirus responsible for an unprecedented outbreak of human encephalitis during 1975-1976 in Sao Paulo State, Brazil. Previous studies have shown an increased number of inflammatory macrophages in the central nervous system (CNS) of ROCV-infected mice, implying a role for macrophages in the pathogenesis of ROCV. Here, we show that ROCV infection results in increased expression of CCL2 in the blood and in infiltration of macrophages into the brain. Moreover, we show, using CCR2 knockout mice, that CCR2 expression is essential for macrophage infiltration in the brain during ROCV infection and that the lack of CCR2 results in increased disease severity and mortality. Thus, our findings show the protective role of CCR2-mediated infiltration of macrophages in the brain during ROCV infection.
Assuntos
Encefalite/metabolismo , Infecções por Flavivirus/metabolismo , Flavivirus/patogenicidade , Macrófagos/metabolismo , Receptores CCR2/metabolismo , Animais , Encéfalo , Brasil , Encefalite/virologia , Feminino , Infecções por Flavivirus/virologia , Macrófagos/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Hydrogen sulfide (H2S) is an endogenous neuromodulator produced mainly by the enzyme cystathionine gamma-lyase (CSE) in peripheral tissues. A pronociceptive role of endogenously produced H2S has been previously reported by our group in a model of orofacial inflammatory pain. Using the established persistent orofacial pain rat model induced by complete Freund's adjuvant (CFA) injection into temporomandibular joint (TMJ), we have now investigated the putative role of endogenous H2S modulating hypernociceptive responses. Additionally, plasmatic extravasation on TMJ was measured following different treatments by Evans blue dye quantification. Thus, rats were submitted to Von Frey and Formalin tests in orofacial region before and after pharmacological inhibition of the CSE-H2S system combined or not with CFA-induced TMJ inflammation. Pretreatment with CSE inhibitor, propargylglycine (PAG; 88.4⯵mol/kg) reduced temporomandibular inflammatory pain when injected locally as well as systemically. In particular, local PAG injection seems to be more effective for hypernociceptive responses in orofacial persistent inflammation since its action is evidenced in the majority analyzed periods of the inflammatory process compared to its systemic use. Moreover, local injection seems to act on temporomandibular vascular permeability, evidenced by decreased plasmatic extravasation induced by local PAG administration. Our data are consistent with the notion that the endogenous synthetized gas H2S modulates persistent orofacial pain responses revealing the pharmacological importance of the CSE inhibitor as a possible therapeutic target for their control.
Assuntos
Cistationina gama-Liase/metabolismo , Dor Facial/enzimologia , Dor Facial/etiologia , Inflamação/complicações , Inflamação/patologia , Articulação Temporomandibular/patologia , Alcinos/uso terapêutico , Análise de Variância , Animais , Inibidores Enzimáticos/uso terapêutico , Dor Facial/complicações , Dor Facial/tratamento farmacológico , Adjuvante de Freund/toxicidade , Glicina/análogos & derivados , Glicina/uso terapêutico , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Inflamação/induzido quimicamente , Masculino , Medição da Dor , Ratos , Ratos Wistar , Fatores de Tempo , Resultado do TratamentoRESUMO
The aim of this study was to evaluate the transitory stress levels and the anxiety state in children submitted to conventional and computerized dental anesthesia. Twenty children (7 to 12 years) were randomly assigned to receive conventional and computerized dental anesthesia. To investigate the hypothesis that transitory stress could be lower after using computerized anesthesia compared to conventional anesthesia, cortisol levels in saliva were measured before and after each technique. Anxiety was also evaluated individually by answering the State-Trait Anxiety Inventory for Children (STAIC). Numerical data were analyzed statistically by the Mann-Whitney non-parametric test (5% significance level). Salivary cortisol levels increased in 8 (40%) patients after conventional anesthesia and in 9 (45%) patients after computerized anesthesia, with no statistically significant difference between the two types (p=0.34). In the same way, no statistically significant difference was found between the techniques (p=0.39) related to the psychological analysis based on the STAIC scores. Local anesthesia using either conventional anesthesia or a computerized delivery system produced similar level of stress/anxiety in pediatric patients, using both quantitative and qualitative analyses.
Assuntos
Anestesia Dentária/métodos , Ansiedade/psicologia , Computadores , Ansiedade ao Tratamento Odontológico , Estresse Psicológico , Criança , Feminino , Humanos , Hidrocortisona/análise , Masculino , Saliva/químicaRESUMO
The aim of this study was to evaluate the transitory stress levels and the anxiety state in children submitted to conventional and computerized dental anesthesia. Twenty children (7 to 12 years) were randomly assigned to receive conventional and computerized dental anesthesia. To investigate the hypothesis that transitory stress could be lower after using computerized anesthesia compared to conventional anesthesia, cortisol levels in saliva were measured before and after each technique. Anxiety was also evaluated individually by answering the State-Trait Anxiety Inventory for Children (STAIC). Numerical data were analyzed statistically by the Mann-Whitney non-parametric test (5% significance level). Salivary cortisol levels increased in 8 (40%) patients after conventional anesthesia and in 9 (45%) patients after computerized anesthesia, with no statistically significant difference between the two types (p=0.34). In the same way, no statistically significant difference was found between the techniques (p=0.39) related to the psychological analysis based on the STAIC scores. Local anesthesia using either conventional anesthesia or a computerized delivery system produced similar level of stress/anxiety in pediatric patients, using both quantitative and qualitative analyses.
O objetivo deste estudo foi avaliar os níveis de estresse transitório e o estado de ansiedade em crianças submetidas à anestesia dental convencional e computadorizada. Vinte crianças (7 a 12 anos de idade) foram randomicamente designadas para receber anestesia dental convencional e computadorizada. Para investigar a hipótese que o estresse transitório poderia ser menor após a anestesia computadorizada, comparada à anestesia convencional, os níveis de cortisol na saliva foram medidos antes e depois de cada técnica. A ansiedade também foi avaliada individualmente por meio do State-Trait Anxiety Inventory for Children (STAIC). Os dados numéricos foram analisados estatisticamente pelo teste não paramétrico de Mann-Whitney (nível de significância de 5%). Os níveis salivares de cortisol aumentaram em 8 (40%) pacientes após anestesia convencional e em 9 (45%) pacientes após anestesia computadorizada, sem diferença estatisticamente significante entre os dois tipos (p=0,34). Da mesma maneira, não foi encontrada diferença estatisticamente significante entre as técnicas (p=0,39) com relação à análise psicológica baseada nos escores STAIC. Anestesia local usando tanto a anestesia convencional quanto o sistema de aplicação computadorizado produziu nível similar de estresse/ansiedade em pacientes infantis, utilizando análises quantitativa e qualitativa. .
Assuntos
Humanos , Masculino , Feminino , Criança , Anestesia Dentária/métodos , Ansiedade/psicologia , Computadores , Ansiedade ao Tratamento Odontológico , Estresse Psicológico , Hidrocortisona/análise , Saliva/químicaRESUMO
The systemic induction of cytokines and prostaglandins plays a key role in the development of fever. However, whether fever is triggered by local injection of lipopolysaccharide (LPS) and the involvement of locally produced prostaglandins in periodontal tissue has never been assessed. Thus, we tested the hypothesis that the trigeminal nerve is a neuronal pathway that signals the brain during acute periodontitis, and this response involves prostaglandin induction. Rats were given a gingival intra-pouch injection of sterile saline or Escherichia coli lipopolysaccharide, at doses of 10 and 100 microg/kg. Some animals were pre-treated with the local anesthetic mepivacaine or had the peripheral branches of the trigeminal nerves transected. Another group of animals were pre-treated (locally or systemically) with the nonselective inhibitor of cyclooxygenases diclofenac. Body core temperature (T (b)) was measured by means of biotelemetry before and after injections. LPS elicited a dose-dependent increase in T (b), which was abolished by mepivacaine, bilateral transection of the peripheral branches of the trigeminal nerve, or local treatment with diclofenac. The results indicate that there is an activation of periodontal nerves to induce fever by LPS. It also shows that local formation of prostaglandins plays a role in fever development. Moreover, immunohistochemistry detected c-fos expression in the subnucleus caudalis of spinal trigeminal nucleus and in the preoptic area of the hypothalamus 2 and 3 h after LPS injection, further confirming the role of trigeminal nerve signaling brain in acute periodontitis.