How do the mindfulness and sensory-behavioural-emotional aspects influence the painful experience related to temporomandibular disorder?

BACKGROUND: Chronic pain is persistent or recurrent pain lasting longer than 3 months. The experience of temporomandibular disorder (TMD)-related pain is modulated by emotional and social factors, with mindfulness encapsulating these aspects. OBJECTIVE: To investigate the association between cognitive-behavioural-emotional characteristics, mindfulness and the painful experience in women with chronic pain-related TMD. METHODS: A cross-sectional study was conducted, including 90 women aged between 18 and 61 years old, diagnosed with chronic pain-related TMD according to the Diagnostic Criteria for Temporomandibular Disorder, considering both temporomandibular joint and muscle pain. Specific instruments were employed to assess cognitive-behavioural-emotional aspects. The Mindful Attention Awareness Scale and the Five Facets of Mindfulness Questionnaire scales evaluated the level and construct of mindfulness. The relationship between variables was analysed using bivariate association tests (.05 > p < .20), followed by multiple regression tests (p < .05). RESULTS: The heightened experience of pain correlated with increasing age, a low level of education, the attribution of the locus of control by chance, and lower levels of mindfulness (p < .05). The heightened experience of pain was negatively influenced by mindfulness levels (p < .05). On the other hand, the painful experience was mainly influenced by facets describing negative formulation, distraction, non-reactivity and non-judgement (p < .05). CONCLUSION: Demographic, cognitive-behavioural-emotional data and levels of mindfulness and its facets presented different influence weights on the painful experience. These findings provide support for future studies focusing on mindfulness strategies, education and pain management in women with chronic pain-related TMD.

Systemic Chronic Treatment with Cannabidiol in Carioca High- and Low-Conditioned Freezing Rats in the Neuropathic Pain Model: Evaluation of Pain Sensitivity.

Studies have shown high comorbidity of anxiety disorder and chronic pain; generalized anxiety disorder (GAD) and neuropathic pain are among these pathologies. Cannabidiol (CBD) has been considered a promising treatment for these conditions. This study investigated whether chronic systemic treatment with CBD alters pain in high- (CHF) and low-freezing (CLF) Carioca rats (GAD model) and control rats (CTL) submitted to chronic neuropathic pain. The rats were evaluated in the sensory aspects (von Frey, acetone, and hot plate tests) before the chronic constriction injury of the ischiatic nerve (CCI) or not (SHAM) and on days 13 and 23 after surgery. Chronic treatment with CBD (5 mg/kg daily) was used for ten days, starting the 14th day after surgery. The open field test on the 22nd also evaluated locomotion and anxiety-like behavior. CBD treatment had an anti-allodynic effect on the mechanical and thermal threshold in all lineages; however, these effects were lower in the CHF and CLF lineages. Considering emotional evaluation, we observed an anxiolytic effect in CTL+CCI and CHF+CCI after CBD treatment and increased mobility in CLF+SHAM rats. These results suggest that the CBD mechanical anti-allodynic and emotional effects can depend on anxiety level.

Inherited pain hypersensitivity and increased anxiety-like behaviors are associated with genetic epilepsy in Wistar Audiogenic Rats: Short- and long-term effects of acute and chronic seizures on nociception and anxiety.

Anxiety and pain hypersensitivity are neurobehavioral comorbidities commonly reported by patients with epilepsies, and preclinical models are suitable to investigate the neurobiology of behavioral and neuropathological alterations associated with these epilepsy-related comorbidities. This work aimed to characterize endogenous alterations in nociceptive threshold and anxiety-like behaviors in the Wistar Audiogenic Rat (WAR) model of genetic epilepsy. We also assessed the effects of acute and chronic seizures on anxiety and nociception. WARs from acute and chronic seizure protocols were divided into two groups to assess short- and long-term changes in anxiety (1 day or 15 days after seizures, respectively). To assess anxiety-like behaviors, the laboratory animals were submitted to the open field, light-dark box, and elevated plus maze tests. The von Frey, acetone, and hot plate tests were used to measure the endogenous nociception in seizure-free WARs, and postictal antinociception was recorded at 10, 30, 60, 120, 180 min, and 24 h after seizures. Seizure-free WARs presented increased anxiety-like behaviors and pain hypersensitivity, displaying mechanical and thermal allodynia (to heat and cold stimuli) in comparison to nonepileptic Wistar rats. Potent postictal antinociception that persisted for 120 to 180 min was detected after acute and chronic seizures. Additionally, acute and chronic seizures have magnified the expression of anxiety-like behaviors when assessed at 1 day and 15 days after seizures. Behavioral analysis indicated more severe and persistent anxiogenic-like alterations in WARs submitted to acute seizures. Therefore, WARs presented pain hypersensitivity and increased anxiety-like behaviors endogenously associated with genetic epilepsy. Acute and chronic seizures induced postictal antinociception in response to mechanical and thermal stimuli and increased anxiety-like behaviors when assessed 1 day and 15 days later. These findings support the presence of neurobehavioral alterations in subjects with epilepsy and shed light on the use of genetic models to characterize neuropathological and behavioral alterations associated with epilepsy.

Emerging role of microglia and astrocyte in the affective-motivational response induced by a rat model of persistent orofacial pain.

Few studies are approaching the neural basis underlying the aggregation of emotional disorders in orofacial pain despite the stress, depression, and anxiety are some of the most commonly reported risk factors. Using a persistent orofacial pain rat model induced by complete Freund's adjuvant (CFA) injection into the temporomandibular joint, we have investigated the plasticity astrocytes and microglia key brain regions for the affective-emotional component of pain. We measured the expression and morphologic pattern of reactivation of glial fibrillary acidic protein (GFAP, astrocyte marker) and Iba-1 (microglial marker) by western blotting and immunohistochemistry analysis. The results showed no alterations on motor activity during inflammatory pain, indicating an exclusive effect of nociceptive behavior on the plasticity of limbic regions. CFA-induced temporomandibular inflammation changed GFAP and Iba-1 expression in distinct regions related to emotional behavior in a time-dependent manner. A significant increase in GFAP and Iba-1 expression was observed in the central nucleus of the amygdala, hippocampus and periaqueductal grey matter from day 3 to day 10 post-CFA injection. Moreover, a positive correlation between GFAP and Iba-1 upregulation and an increased mechanical hypersensitivity was observed. Conversely, no change on GFAP and Iba-1 expression was observed in the hypothalamus and colliculus during orofacial inflammatory pain. Our data suggest an important role for glial cells in the affective-motivational dimension of orofacial pain beyond their well-explored role in the traditional nociceptive transmission circuits.

Application of photobiomodulation for chronic pain-related TMD on pain points versus pre-established points: Randomized clinical trial.

Photobiomodulation therapy (PTB) is a therapeutic possibility for temporomandibular disorders (TMD), but its effectiveness and protocols for use remain controversial. This study is a RCT that compared the effectiveness of PTB on pain points of the masticatory muscles and TMJs, located through palpation versus application of pre-established points in women with painful TMD, diagnosis by DC/TMD (Diagnostic Criteria for Temporomandibular Disorders - Brazilian Portuguese version). Therefore, a total sample of 54 women, aged between 18 and 60 years, was investigated. Volunteers were randomly randomized and PTB was applied in four different groups with a dose of 4 J and 6 J divided into pre-established application points (PE - G1) and pain points (PD - G2) - Groups 4PE, 4PD, 6PE and 6PD. Four laser applications were performed with a wavelength of 780 nm, one session per week, totaling one month of therapy. The following assessments were performed: DC/TMD, Brief Pain Inventory (BPI), McGill Questionnaire - Short Version (SF-MPQ) and Pain Intensity, Visual Analogue Scale (VAS). Friedman's test was used for within-group comparisons, while the Mann-Whitney test was used for between-group comparisons (p < 0.05). According to the results, laser application on pain points (G2) was more effective. McGill's results showed that regardless of dose, the pain point application group had better outcomes (p = 0.004). Pain intensity evaluation (last days) also showed that application at the pain points was more effective regardless of dose (p = 0.0002). Medians and interquartile deviations showed overall that PTB was more effective at pain points, with a trend towards better outcomes at the 6 J dose. Therefore, it can be concluded that in women with chronic painful TMD, the application of PTB at pain points is more effective than the application at pre-established points. Therefore, individualized PTB protocols are proposed, based on examination palpation of the masticatory structures.

Chronic Pain and Cannabidiol in Animal Models: Behavioral Pharmacology and Future Perspectives.

The incidence of chronic pain is around 8% in the general population, and its impact on quality of life, mood, and sleep exceeds the burden of its causal pathology. Chronic pain is a complex and multifaceted problem with few effective and safe treatment options. It can be associated with neurological diseases, peripheral injuries or central trauma, or some maladaptation to traumatic or emotional events. In this perspective, animal models are used to assess the manifestations of neuropathy, such as allodynia and hyperalgesia, through nociceptive tests, such as von Frey, Hargreaves, hot plate, tail-flick, Randall & Selitto, and others. Cannabidiol (CBD) has been considered a promising strategy for treating chronic pain and diseases that have pain as a consequence of neuropathy. However, despite the growing body of evidence linking the efficacy of CBD on pain management in clinical and basic research, there is a lack of reviews focusing on chronic pain assessments, especially when considering pre-clinical studies, which assess chronic pain as a disease by itself or as a consequence of trauma or peripheral or central disease. Therefore, this review focused only on studies that fit our inclusion criteria: (1) used treatment with CBD extract; (2) used tests to assess mechanical or thermal nociception in at least one of the following most commonly used tests (von Frey, hot plate, acetone, Hargreaves, tail-flick, Randall & Selitto, and others); and (3) studies that assessed pain sensitivity in chronic pain induction models. The current literature points out that CBD is a well-tolerated and safe natural compound that exerts analgesic effects, decreasing hyperalgesia, and mechanical/thermal allodynia in several animal models of pain and patients. In addition, CBD presents several molecular and cellular mechanisms of action involved in its positive effects on chronic pain. In conclusion, using CBD seems to be a promising strategy to overcome the lack of efficacy of conventional treatment for chronic pain.

D2-like receptor activation by intranasal dopamine attenuates fear responses induced by electrical stimulation of the dorsal periaqueductal grey matter, but fails to reduce aversion to pit vipers and T-maze performance.

BACKGROUND: Panic-like reactions elicited by electrical stimulation of the dorsal periaqueductal grey matter (ES-dPAG) seem to be regulated by dopamine (DA). We showed that DA applied intranasally (IN) increased escape-behaviour thresholds induced by ES-dPAG of rats, indicating a panicolytic-like effect. AIMS: We investigated whether IN-DA increases escape-response thresholds induced by ES-dPAG by acting on D2-like receptors, and whether IN-DA affects escape responses elicited by the presence of a potential predator and by open space and height of the elevated T-maze (ETM) as well as motor performance in the open field (OF) test. METHODS: Wistar rats exposed to ES-dPAG were treated with Sulpiride (SUL, 40 mg/kg, D2-like receptor antagonist) previously IN-DA (2 mg/kg). Independent groups of rats treated with IN-DA were submitted to prey versus snake paradigm (PSP), ETM and OF. RESULTS: Anti-aversive effects of the IN-DA were reduced by SUL pretreatment in the ES-dPAG test. IN-DA did not affect the escape number in the PSP nor the escape latencies in the ETM as well as motor performance in the OF. CONCLUSIONS/INTERPRETATION: The IN-DA effects in reducing unconditioned fear responses elicited by ES-dPAG seem to be mediated by D2-like receptors. The lack of effects on panic-related responses in the ETM and PSP may be related to the possibility of avoiding the danger inherent to these models, a defence strategy not available during ES-dPAG. These findings cannot be attributed to motor performance. The decision-making responses to avoid dangerous situations can be orchestrated by supra-mesencephalic structures connected by non-dopaminergic inputs.

Phenotypic analysis of discordant monozygotic twins for pain-related temporomandibular joint disorder. Case report / Análise fenotípica de gêmeas monozigóticas discordantes para disfunção temporomandibular dolorosa. Relato de caso

ABSTRACT BACKGROUND AND OBJECTIVES: The design of research with monozygotic twins discordant for the disease has emerged as a powerful tool for the detection of phenotypic risk factors. The aim of this study is to report a clinical case of monozygotic twins discordant for pain-related temporomandibular joint disorder (TMD) from a cognitive-behavioral-emotional phenotypic analysis, from the comparison of clinical variables of pain, history of exposure to painful procedures in early childhood, and coping with pain. CASE REPORT: TMD-Twin presented a diagnosis of painful (myofascial pain with referral) and joint (disk displacement with reduction) TMD according to the criteria of the DC/TMD. Control-Twin did not show TMD, however she presented other chronic pains. TMD-Twin showed reduced pressure pain threshold, hyperalgesia in trigeminal and extra-trigeminal regions compared to the Control-Twin. TMD-Twin was more exposed to painful procedures and emotional events due to congenital heart problems. Both had central sensitization based on the Central Sensitization Inventory, although TMD-Twin had more catastrophic thoughts about pain. TMD-Twin presented an internal locus of control. CONCLUSION: Both monozygotic twins presented a chronic pain phenotype, although they were discordant with the TMD-related pain. The main differences were the lower pressure pain threshold and higher hyperalgesia locally presented by TMD-Twin. The internal locus of control indicates greater pain sensitivity, with better coping of the painful experience for the TMD-Twin. One possible explanation for this clinical condition can be that painful experiences in early childhood have shaped a phenotype of greater sensitivity with better coping and resilience to the painful condition.

RESUMO JUSTIFICATIVA E OBJETIVOS: O desenho da pesquisa com gêmeos monozigóticos discordantes para a doença surgiu como uma ferramenta poderosa para a detecção de fatores de risco fenotípicos. O objetivo deste estudo foi relatar um caso clínico de gêmeas monozigóticas discordantes para disfunção temporomandibular (DTM) dolorosa a partir de análise fenotípica cognitivo-comportamental-emocional entre elas, por meio de comparação de variáveis clínicas de dor, histórico de exposição a procedimentos dolorosos na primeira infância e enfrentamento de dor (autoeficácia e lócus de controle). RELATO DO CASO: A gêmea-DTM apresentou diagnóstico de DTM dolorosa (dor miofascial com referência) e articular (deslocamento do disco com redução) segundo os critérios do Critérios de Diagnóstico para Distúrbios Temporomandibulares. A gêmea--controle não apresentou DTM, contudo apresentou manifestação clínica de outras dores crônicas. A gêmea-DTM apresentou limiar de dor à pressão reduzido, hiperalgesia em regiões trigeminais/extra-trigeminais quando comparados à gêmea-controle, que na primeira infância foi mais exposta a procedimentos dolorosos devido a problemas cardíacos congênitos. Ambas apresentaram sensibilização central de acordo com o Inventário de Sensibilização Central, embora a gêmea-DTM apresentou mais pensamentos catastróficos sobre a dor. A gêmea-DTM apresentou lócus de controle interno. CONCLUSÃO: Ambas as gêmeas apresentaram fenótipo de dor crônica, apesar do fato de serem discordantes para a DTM. Dentre as avaliações, as que mais diferiram entre o par foram o baixo limiar de dor à pressão e hiperalgesia local presentes na gêmea com DTM. O lócus de controle interno associado à maior sensibilidade indicou melhor enfrentamento da experiência dolorosa para a gêmea-DTM. Uma possível explicação para esta manifestação clínica está pautada na hipótese de que experiências dolorosas na primeira infância vivenciadas por ela tenham moldado um fenótipo de maior sensibilidade com melhor enfrentamento e resiliência frente à condição dolorosa.

Increased TRPV1 Channels and FosB Protein Expression Are Associated with Chronic Epileptic Seizures and Anxiogenic-like Behaviors in a Preclinical Model of Temporal Lobe Epilepsy.

Epilepsies are neurological disorders characterized by chronic seizures and their related neuropsychiatric comorbidities, such as anxiety. The Transient Receptor Potential Vanilloid type-1 (TRPV1) channel has been implicated in the modulation of seizures and anxiety-like behaviors in preclinical models. Here, we investigated the impact of chronic epileptic seizures in anxiety-like behavior and TRPV1 channels expression in a genetic model of epilepsy, the Wistar Audiogenic Rat (WAR) strain. WARs were submitted to audiogenic kindling (AK), a preclinical model of temporal lobe epilepsy (TLE) and behavioral tests were performed in the open-field (OF), and light-dark box (LDB) tests 24 h after AK. WARs displayed increased anxiety-like behavior and TRPV1R expression in the hippocampal CA1 area and basolateral amygdala nucleus (BLA) when compared to control Wistar rats. Chronic seizures increased anxiety-like behaviors and TRPV1 and FosB expression in limbic and brainstem structures involved with epilepsy and anxiety comorbidity, such as the hippocampus, superior colliculus, and periaqueductal gray matter. Therefore, these results highlight previously unrecognized alterations in TRPV1 expression in brain structures involved with TLE and anxiogenic-like behaviors in a genetic model of epilepsy, the WAR strain, supporting an important role of TRPV1 in the modulation of neurological disorders and associated neuropsychiatric comorbidities.

The activation of D2-like receptors by intranasal dopamine facilitates the extinction of contextual fear and prevents conditioned fear-induced antinociception.

Fear extinction (FExt) is used to treat patients with posttraumatic stress disorder (PTSD). However, fear related to traumatic events can be persistent and return even after successful extinction. The neurochemical control of extinction seems to be performed by several neurotransmitters, including dopamine (DA), through D1 and D2 receptors. Recently, we showed that intranasally applied DA (IN-DA) facilitated the FExt, but the mechanisms by which it promoted this effect are still unknown. This study focused on investigating whether these effects are mediated by the action of DA on D2-like receptors since these receptors seem to be related to neurochemical and molecular changes underlying extinction. Also, we investigated whether IN-DA treatment would affect conditioned fear-induced antinociception (Fear-IA). Rats treated with IN-DA (1 mg/kg) twenty-five minutes after sulpiride (SUL; 40 mg/kg, i.p., D2-antagonist) were subjected to the extinction of contextual fear. IN-DA applied before the extinction session induced the FExt and prevented Fear-IA. These effects were impaired by pre-treatment with SUL, suggesting that the IN-DA effects are mediated by DA on D2-like receptors. SUL per se also facilitated the FExt but did not affect Fear-IA. These data suggest IN-DA as a promising pharmacological tool to supplement the psychotherapy of patients suffering from PTSD.

Follow-up results of a randomized clinical trial for low-level laser therapy in painful TMD of muscular origins.

Objective: To characterize short- and long-term assessment of the low-intensity laser therapy (LLLT) effectiveness in women with TMD of muscular origins and to evaluate whether the information about the treatment received (active or placebo) modifies the pain intensity.Methods: Forty-one women with painful TMD (31.7 ± 5.2 years) were divided into laser (n = 20) and placebo (n = 21) groups. The pain intensity was measured at the baseline, after the LLLT (T8), 6 and 12 months. At the 6-month follow-up, the groups received information about the active or placebo treatment.Results: At T8 and 6-month, both active and placebo LLLT were effective in reducing pain (p < .05). After one year, the groups showed similar pain. Active LLLT was more effective in reducing pain palpation (p = .001) and referred pain (p = .04) in the region of the TMJs. The information about the treatment modified the perceived pain intensity.Conclusion: Active and placebo LLLT are effective for painful TMD of muscular origins in the short-term. Information about the treatment impairs the subjective perception of pain.

Intervenção baseada em mindfulness reduz parâmetros de sensibilidade em mulheres com DTM dolorosa crônica / Mindfulness-based intervention reduces sensitivity parameters in women with chronic painful TMD / La intervención basada en la atención plena reduce los parámetros de sensibilidad en mujeres con TMD dolorosa crónica

OBJETIVO: analisar parâmetros clínicos sugestivos de sensibilização central em mulheres com disfunção temporomandibular dolorosa crônica antes e após uma intervenção baseada em mindfulness. MÉTODO: onze mulheres com idade entre 27 e 44 anos (36,36 ± 5,61), com diagnóstico de disfunções temporomandibulares dolorosa crônica (Diagnostic Criteria for Temporomandibular Disorders), participaram do estudo. A hiperalgesia, a alodinia e o limiar de dor à pressão foram avaliados em pontos trigeminais e extra-trigeminais antes e após a intervenção baseada em mindfulness, bem como a aplicação do questionário Mindful Attention Awareness Scale. O programa de mindfulness de 8 semanas foi oferecido às participantes do estudo, com base no protocolo Mindfulness Trainings International, em sessões semanais de 2 horas e uma sessão de 4 horas. RESULTADOS: houve redução significativa da alodinia, da hiperalgesia e aumento do limiar de dor à pressão, além de aumento significativo do nível de atenção plena (p < 0,05) enquanto marcador de efetividade da intervenção baseada em mindfulness oferecida. CONCLUSÃO: índices mais saudáveis nos parâmetros clínicos sugestivos de sensibilização central investigados após a intervenção, representam melhora significativa na relação da pessoa com quadro de enfermidade crônica geradora de experiências desagradáveis contínuas como a disfunções temporomandibulares.

OBJECTIVE: manifestations of allodynia and hyperalgesia are commonly present in chronic painful temporomandibular disorder. Studies point to the benefits of people with chronic pain undergoing mindfulness-based interventions, by demonstrating brain, hormonal, and clinical changes. This study aimed to analyze clinical parameters suggestive of central sensitization (pressure pain threshold, allodynia, and hyperalgesia) in women with chronic painful temporomandibular disorder before and after a mindfulness-based intervention, through a before-and-after intervention study, longitudinal, uncontrolled. METHOD: the analysis included 11 women chosen at random from a total of 20, aged between 27 and 44 years (36.36 ± 5.61), diagnosed with chronic painful temporomandibular disorder according to the Diagnostic Criteria for Temporomandibular Disorders protocol and who completed the 8-week mindfulness-based intervention program. Hyperalgesia, allodynia, and pressure pain threshold were tested at trigeminal and extra-trigeminal points before and after the intervention as well as the application of the questionnaire to measure the level of mindfulness (Mindful Attention Awareness Scale). The 8-week mindfulness program was offered to the study participants, based on the Mindfulness Trainings International - protocol, in weekly 2-hour sessions and a 4-hour session (immersion). RESULTS: the results pointed to a reduction in allodynia, hyperalgesia and an increase in pressure pain threshold, with significant differences in several tested points (p <0.05). The changes identified were accompanied by a significant increase in the level of mindfulness (p < 0.05). CONCLUSION: healthier indexes in clinical parameters suggestive of central sensitization investigated after the intervention represent a significant improvement in the person's relationship with a chronic illness that generates continuous unpleasant experiences such as temporomandibular disorder. Thus, the practice of mindfulness represents an appropriate and particularly interesting care because it is a low-cost, non-invasive intervention with low evidence of adverse effects.

OBJETIVO: las manifestaciones de alodinia y hiperalgesia y están comúnmente presentes en lo trastorno temporomandibular doloroso crónico. Los estudios señalan los beneficios de las personas con dolor crónico que se someten a intervenciones basadas en la atención plena, al demostrar cambios cerebrales, hormonales y clínicos. El objetivo de este estudio fue analizar parámetros clínicos sugestivos de sensibilización central (umbral de dolor por presión, alodinia e hiperalgesia) en mujeres con trastorno temporomandibular doloroso crónico antes y después de una intervención basada en la atención plena, a través de un estudio de intervención antes y después, longitudinal, sin control. MÉTODO: el análisis incluyó a 11 mujeres elegidas al azar de un total de 20, con edades entre 27 y 44 años (36.36 ± 5.61), diagnosticadas con trastorno temporomandibular doloroso crónico de acuerdo con protocolo Criterios de diagnóstico para trastornos temporomandibulares y que completaron el 8- programa de intervención basado en mindfulness de una semana. La hiperalgesia, la alodinia y el umbral de dolor por presión se probaron en los puntos trigémino y extra-trigémino antes y después de la intervención, así como también en la aplicación del cuestionario para medir el nivel de atención plena (Escala de conciencia de atención plena). El programa de atención plena de 8 semanas se ofreció a los participantes del estudio, basado en el protocolo Mindfulness Trainings International, en sesiones semanales de 2 horas y una sesión de 4 horas (inmersión). RESULTADOS: los resultados apuntaron a una reducción en la alodinia, hiperalgesia y un aumento en la umbral de dolor por presión, con diferencias significativas en varios puntos probados (p <0.05). Los cambios identificados fueron acompañados por un aumento significativo en el nivel de atención plena (p <0.05), como un marcador de la efectividad de la capacitación ofrecida para la práctica de la atención plena. CONCLUSIÓN: los índices más saludables en los parámetros clínicos sugestivos de sensibilización central investigados después de la intervención, representan una mejora significativa en la relación de la persona con una enfermedad crónica que genera experiencias continuas desagradables como trastorno temporomandibular doloroso crónico. Por lo tanto, la práctica de la atención plena representa una atención aplicable y particularmente interesante porque es una intervención no invasiva de bajo costo con poca evidencia de efectos adversos.

Sepsis-induced encephalopathy impairs descending nociceptive pathways in rats.

Sepsis-associated encephalopathy (SAE) is a significant problem in patients with sepsis, and it is associated with a decrease in cognitive and sensitivity capability induced by systemic inflammation. SAE is implicated in reversible brain damage of several regions related to cognition, emotion, and sensation; however, it is not well established if it could affect brain regions associated with nociceptive modulation. Here were evaluated the nociceptive thresholds in rats with systemic inflammation induced by cecal ligation puncture (CLP). After 24 h of CLP, it was observed an increase in nociceptive threshold in all tests. Periaqueductal gray, rostroventral medulla, critical regions for descending nociceptive modulation, were evaluated and showed enhanced pro-inflammatory cytokines as well as glial activation. These results suggest that systemic inflammation could compromise descending facilitatory pathways, impairing nociceptive sensory functioning.

Intranasal dopamine attenuates fear responses induced by electric shock to the foot and by electrical stimulation of the dorsal periaqueductal gray matter.

PURPOSE: Intranasally applied dopamine (IN-DA), which likely reaches the brain via nasal-brain pathways and bypasses the blood-brain barrier, has been found to increase extracellular DA and bind to the DA2 transporter in the striatum. Recent studies suggest that DA plays a significant role in the processing of signaled and unconditioned aversive stimulation, including evidence that may attenuate responses to painful input. The purpose of this study was to examine the effects of IN-DA on fear-related behaviors induced by electric shock to the foot or by electrical stimulation of the dorsal periaqueductal gray matter (dPAG). METHODS: DA hydrochloride suspended in a viscous castor oil gel (1 or 2 mg/kg) was applied (IN-DA) in a volume of 5 µL into the nostrils of adult Wistar male rats in order to evaluate its effects on (a) freezing induced by electric shock to the foot and (b) thresholds of freezing and escape and duration of post-stimulation freezing induced by electrical stimulation of the dPAG. RESULTS: IN-DA attenuated freezing induced by electric shock to the foot in the three test trials, indicating that it reduced long-term fear responses. IN-DA also increased the threshold of dPAG stimulation-induced escape responses and reduced post-stimulation freezing. CONCLUSIONS: IN-DA, which has previously been shown to facilitate learning and to have antidepressive-like effects, attenuated unconditioned fear responses elicited by peripheral and intramesencephalic (dPAG) stimulation and reduced long-term conditioned fear responses.

The Effects of Cobalt Protoporphyrin IX and Tricarbonyldichlororuthenium (II) Dimer Treatments and Its Interaction with Nitric Oxide in the Locus Coeruleus of Mice with Peripheral Inflammation.

Heme oxygenase 1 (HO-1) and carbon monoxide were shown to normalize oxidative stress and inflammatory reactions induced by neuropathic pain in the central nervous system, but their effects in the locus coeruleus (LC) of animals with peripheral inflammation and their interaction with nitric oxide are unknown. In wild-type (WT) and knockout mice for neuronal (NOS1-KO) or inducible (NOS2-KO) nitric oxide synthases with inflammatory pain induced by complete Freund's adjuvant (CFA), we assessed: 1) antinociceptive actions of cobalt protoporphyrin IX (CoPP), an HO-1 inducer; 2) effects of CoPP and tricarbonyldichlororuthenium(II)dimer (CORM-2), a carbon monoxide-liberating compound, on the expression of HO-1, NOS1, NOS2, CD11b/c, GFAP,and mitogen-activated protein kinases (MAPK)in the LC. CoPP reduced inflammatory pain in different time-dependent manners in WT and KO mice. Peripheral inflammation activated astroglia in the LC of all genotypes and increased the levels of NOS1 and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK 1/2) in WT mice. CoPP and CORM-2 enhanced HO-1 and inhibited astroglial activationin all genotypes. Both treatments blocked NOS1 overexpression,and CoPP normalized ERK 1/2 activation. This study reveals an interaction between HO-1 and NOS1/NOS2 during peripheral inflammation andshows that CoPP and CORM-2 improved HO-1 expression and modulated the inflammatory and/or plasticity changes caused by peripheral inflammation in the LC.

Exodontia-induced muscular hypofunction by itself or associated to chronic stress impairs masseter muscle morphology and its mitochondrial function.

Stress is associated with orofacial pain sensitivity and is qualified as a temporomandibular disorder risk factor. During stressful periods, painful thresholds of masticatory muscles in individuals suffering muscle facial pain are significantly lower than in controls, but the exact physiologic mechanism underlying this relation remains unclear. Our hypothesis is that chronic unpredictable stress and masticatory hypofunction induce morphologic and metabolic masseter muscle changes in rats. For test this hypothesis, adult Wistar rats were submitted to chronic unpredictable stress and/or exodontia of left molars and the left masseter muscle was removed for analysis. The parameters evaluated included ultrastructure, oxidative level, metabolism activity and morphological analysis in this muscle. Our data show by histological analysis, that stress and exodontia promoted a variation on diameters and also angled contours in masseter fibers. The masticatory hypofunction increased oxidative metabolism as well as decreased reactive species of oxygen in masseter muscle. The ultrastructural analysis of muscle fibers showed disruption of the sarcoplasmic reticulum cisterns in certain regions of the fiber in stress group, and the disappearance of the sarcoplasmic reticulum membrane in group with association of stress and exodontia. Our findings clarify mechanisms by which chronic stress and masticatory hypofunction might be involved in the pathophysiology of muscular dysfunctions. Masticatory hypofunction influenced oxidative stress and induced oxidative metabolism on masseter muscle, as well as altered its fiber morphology. Chronic stress presented malefic effect on masseter morphology at micro and ultra structurally. When both stimuli were applied, there were atrophic fibers and a complete mitochondrial derangement.

Restricted lesions of the ventrolateral or dorsal columns of the periaqueductal gray promotes distinct effects on tonic immobility and defensive analgesia in guinea pigs.

Tonic immobility (TI) is an innate defensive response exhibited by prey when physical contact with a predator is prolonged and inescapable. This defensive response is able to activate analgesia mechanisms; this activation has adaptive value because, during an attack by a predator, the manifestation of recuperative behaviors can affect the appropriate behavioral defense strategy. Some studies have suggested that similar structures of the central nervous system can regulate the response of both TI and nociception. Thus, this study evaluated the effect of chemical lesion through the administration of ibotenic acid in restricted brain areas of the periaqueductal gray matter (PAG) in guinea pig on the TI response and nociception evaluated in the hot plate test before and after emission of TI. The data showed that an irreversible chemical lesion in the ventrolateral PAG reduced of the TI response as well as defensive antinociception. However, a lesion in the dorsal PAG blocked the defensive antinociception induced by TI but did not alter TI duration. In summary, one could hypothesize that the neural substrates responsible for defensive behavior and antinociception represent similar systems that are distinct in modulation. Thus, the ventrolateral PAG has been associated with the modulation of TI and the defensive antinociception induced by TI. In contrast, the integrity of the dorsal PAG should be necessary for defensive antinociception to occur but not to elicit TI behavior in guinea pigs.

Enhanced expression of heme oxygenase-1 in the locus coeruleus can be associated with anxiolytic-like effects.

Some researchers have shown that carbon monoxide (CO) plays a role in emotional behavior modulation through intracellular 3'-5'-guanosine monophosphate mechanisms in the locus coeruleus (LC). In fact, the LC region has a high expression of the heme-oxygenase (HO) enzymes, which are responsible for the production of CO. However, the physiological mechanism by which the HO-CO pathway participates in the modulation of emotional responses in the LC still needs clarification. This study evaluates whether a systemic intraperitoneal treatment is able to alter behavioral responses (in the elevated plus-maze and the light-dark box test) and the expression of the HO-1 and HO-2 enzymes in the LC. The tested treatments are acute (3h before) or chronic (twice daily for 10days) and with a carbon monoxide releaser (tricarbonyldichlororuthenium [II] dimer, or CORM-2) or with a HO-1 inducer compound (cobalt protoporphyrin IX, CoPP). The results for the elevated plus-maze show that CO-for both acute or chronic administration of either drug-ncreased the number of entries into the open arms and the percentage of time spent in the open arms. Regarding the light-dark box test, chronic treatment with either drug increased the time spent in the light compartment. Additionally, treatment with CORM-2 or CoPP, either acutely or chronically, increased HO-1 enzyme expression in the LC cells. This study shows that systemic CO treatment can promote an anxiolytic-like effect and the expression of HO-1 enzymes in LC cells.

Similar effect of CRF1 and CRF2 receptor in the basolateral or central nuclei of the amygdala on tonic immobility behavior.

Studies have used paradigms based on animal models to understand human emotional behavior because they appear to be correlated with fear- and anxiety-related defensive patterns in non-human mammals. In this context, tonic immobility (TI) behavior is an innate response associated with extreme threat situations, such as predator attack. Some reports have demonstrated the involvement of corticotropin-releasing factor (CRF) in regulation of the endocrine system, defensive behaviors and behavioral responses to stress. Particularly, a previous study showed that the activation of CRF receptors in the basolateral (BLA) or central (CeA) nuclei of the amygdala increased TI responses, whereas treatment with a non-selective CRF antagonist, alpha-helical-CRF9-41, decreased this innate fear response. However, while CRF1 receptors have pronounced effects in stress-induced anxiety, CRF2 receptors appear be involved in the expression of both stress-induced anxiety and spontaneous anxiety behavior. In this study, we investigated the effects of specific CRF receptors, CRF1 and CRF2, in the BLA and CeA on the duration of TI in guinea pigs. The results show that blockade of CRF1 and CRF2 receptors in the BLA and CeA produces a decrease in fear and/or anxiety, as suggested by a decrease in TI duration in the guinea pigs. Additionally, the specific antagonists for CRF1 and CRF2 receptors were able to prevent the increase in TI duration induced by CRF administration at the same sites. These results suggest that the modulation of fear and anxiety by the CRF system in the BLA and CeA occurs through concomitant effects on CRF1 and CRF2 receptors.

Non-specific effects and clusters of women with painful TMD responders and non-responders to LLLT: double-blind randomized clinical trial.

The aim was to analyze the non-specific effects (placebo, spontaneous remission, and regression to the mean) of the low-level laser therapy (LLLT) in women with myofascial pain (painful temporomandibular disorder (TMD)), as well as to differentiate between responders and non-responder clusters to active and placebo LLLT according to the anxiety levels, salivary cortisol, use of oral contraceptives, and premenstrual period. Sixty-four women diagnosed with myofascial pain (Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD)) were included, divided into laser (n = 20), placebo group (n = 21), and 23 controls (without treatment (WT)). The LLLT applied was 780 nm, masseter and temporal = 5 J/cm2 (20 mW-0.5 W/cm2), and TMJ area = 7.5 J/cm2 (30 mW-0.8 W/cm2), eight sessions, twice a week. The pain intensity (visual analogue scale (VAS)), anxiety (Beck Anxiety Inventory), salivary cortisol, and menstrual cycle's data at the baseline, T1-T8, and 30 days after LLLT (follow-up) were evaluated. The laser group showed 80% of pain reduction, placebo 85%, and WT 43% in T8. Women with severe anxiety and at the premenstrual period did not reduce pain with any LLLT. Active and placebo LLLT had similar effectiveness during the treatment period; however, women with moderate anxiety, cortisol levels above 10 ng/ml, and without contraceptive use maintain analgesia longer with active LLLT than placebo (follow-up 30 days). Women with low levels of anxiety, salivary cortisol below 10 ng/ml, and with contraceptive use showed the higher pain reduction. The analgesia promoted by LLLT in women with myofascial pain is a result of non-specific effects during the treatment period, although active LLLT is more effective in maintaining the analgesia after treatment (30 days) for the cluster of women with moderate anxiety, salivary cortisol above 10 ng/ml, and without contraceptive use.