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.

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.

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.

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.

Effectiveness of low-level laser therapy on pain intensity, pressure pain threshold, and SF-MPQ indexes of women with myofascial pain.

Women with temporomandibular disorders (TMD) frequently report pain areas in body regions. This process is associated with central sensitization phenomena, present in chronic pain. The low-level laser therapy (LLLT) has been reported as a therapeutic option for the painful TMD treatment. The aim of this study was to analyze the effect of LLLT on pain intensity (visual analogue scale, VAS), pain sensitivity in orofacial and corporal points (pressure pain threshold, PPT), and on Short Form-McGill Pain Questionnaire (SF-MPQ) indexes of women with myofascial pain (subtype of muscle TMD). Ninety-one women (18-60 years) were included in the study, among which 61 were diagnosed with myofascial pain (Research Diagnostic Criteria for Temporomandibular Disorder-Ia and Ib) and were divided into laser (n = 31) and placebo group (n = 30), and 30 were controls. The LLLT was applied at pre-established points, twice a week, eight sessions (780 nm; masseter and anterior temporal = 5 J/cm2, 20 mW, 10 s; TMJ area = 7.5 J/cm2, 30 mW, 10 s). Pain intensity, pain sensitivity, and the SF-MPQ indexes were measured at the baseline, during laser sessions, and 30 days after treatment. For intra-group comparisons, the Friedman test was performed, and for inter-group, the Mann-Whitney test. Increased pain sensitivity was found in women with myofascial pain when compared to controls (p < 0.05). There was a reduction in pain intensity for both groups after LLLT. The LLLT did not change the PPT for any group (p > 0.05). Active laser and placebo reduced the indexes of sensory, total pain, and VAS, maintaining the results after 30 days; there was a reduction in the affective pain rating index for both groups, with no maintenance after 30 days for placebo, and the present pain intensity decreased in the laser group and did not change in the placebo after LLLT. In conclusion, the LLLT active or placebo are effective in reducing the overall subjective perception of myofascial pain (VAS and SF-MPQ indexes); however, they have no effectiveness in reducing the pain sensitivity in orofacial and corporal points (PPT increase).

Experimental tooth movement and photobiomodulation on bone remodeling in rats.

Photobiomodulation (PBM) is a therapy induced by a specific type of laser that affects biologic systems through non-thermal ways. The study of its basic mechanism has gained interest since little is known about the causes of the different effects of this treatment. In the present study, we investigated the action of the PBM application rate changes in the peri-implant tissues in rats subjected to tooth movement in different periods. Wistar rats (±250 g) received an apparatus in the region of the central incisors superiors tightly (70 g) or not, and they were also subjected to one or three PBM sessions. After 7 or 14 days, the rats were subjected to euthanasia and the jaws were dissected and processed for histology. For analysis, serial sections were made that were stained by Picrosirius Red for analysis of collagen fibers, Masson's trichrome for newly formed bone scan, and Hematoxylin-Eosin for quantification of osteoblasts. PBM applied in one or three sessions increased the population of osteoblasts. Still, the application of three sessions of PBM increased the density of collagen fibers and new bone formation compared to the controls. An increase was observed in the interincisal distance in irradiated groups with three PBM sessions and the application of force for both 7 or 14 days. These findings suggest that PBM can contribute positively to the orthodontic movement. So the laser therapy can be used as an adjunct procedure to be performed concurrently for orthodontic treatment in the dental clinic.

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.

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.

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.

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.

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.

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.

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.

Tooth movement activates the central amygdala and the lateral hypothalamus by the magnitude of the force applied.

OBJECTIVE: To determine if the magnitude of the force used to induce incisor tooth movement promotes distinct activation in cells in the central amygdala (CEA) and lateral hypothalamus (LH) of rats. Also, the effect of morphine on Fos immunoreactivity (Fos-IR) was investigated in these nuclei. MATERIALS AND METHODS: Adult male rats were anesthetized and divided into six groups: only anesthetized (control), without orthodontic appliance (OA), OA but without force, OA activated with 30g or 70g, OA with 70g in animals pretreated with morphine (2 mg/kg, intraperitoneal). Three hours after the onset of the experiment the rats were reanesthetized and perfused with 4% paraformaldehyde. The brains were removed and fixed, and sections containing CEA and LH were processed for Fos protein immunohistochemistry. RESULTS: The results show that in the control group, the intramuscular injection of a ketamine/ xylazine mixture did not induce Fos-IR cells in the CEA or in the LH. Again, the without force group showed a little Fos-IR. However, in the 70g group the Fos-IR was the biggest observed (P < .05, Tukey) in the CEA and LH compared with the other groups. In the 30g group, the Fos-IR did not differ from the control group, the without OA group, and the without force group. Furthermore, pretreatment with morphine in the 70g group reduced Fos-IR in these regions. CONCLUSIONS: Tooth movement promotes Fos-IR in the CEA and LH according to the magnitude of the force applied.

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.

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.

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.

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.