Depressive behavior induced by unpredictable chronic mild stress increases dentin hypersensitivity in rats

Archives of Oral Biology 80 (2017) 164–174

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Archives of Oral Biology journal homepage: www.elsevier.com/locate/archoralbio

Depressive behavior induced by unpredictable chronic mild stress increases dentin hypersensitivity in rats

MARK

Fabiane Martins Barbosaa, Danilo Cabralb, Fernanda Kabadayana, Eduardo Fernandes Bondanb, Maria de Fátima Monteiro Martinsb, Thiago Berti Kirstenb, Leoni Villano Bonaminb, ⁎ Nicolle Queiroz-Hazarbassanovc, Maria Martha Bernardia,b, , Cintia Helena Coury Saracenia a b c

Graduate Program in Dentistry, Paulista University, Rua Dr. Bacelar, 1212, São Paulo, SP 04026-002, Brazil Environmental and Experimental Pathology, Paulista University, Rua Dr. Bacelar, 1212, São Paulo, SP 04026-002, Brazil Department of Pathology, School of Veterinary Medicine, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva, 87, São Paulo, SP 05508-270, Brazil

A R T I C L E I N F O

A B S T R A C T

Keywords: Nociceptive behavioral response Corticosterone Tumor necrosis factor-alpha Astrocytes Dentin sensitivity Depression

Objective: The present study evaluated the nociceptive response induced by dentin hypersensitivity after dental erosion in rats that were exhibited to unpredictable chronic mild stress (UCMS)-induced depressive-like behavior. Design: Adult male rats were subjected to UCMS (depression [D] group) or not (no depression [ND] group) for 30 days and received either acidic solution to induce dental erosion (E) or water (W), thus forming the WND, END, WD, and ED groups. After the end of treatment, depressive-like parameters (i.e., sucrose preference and immobility in the forced swim test) and dentin hypersensitivity were evaluated. Plasma tumor necrosis factor α (TNF-α) and corticosterone levels were measured, and astrocytic glial fibrillary acidic protein (GFAP) expression was evaluated in the prefrontal cortex, hippocampus, amygdala, and hypothalamus. Results: Administration of the acidic solution potentiated dentin hypersensitivity and increased corticosterone levels in the ED group compared with the WD group. TNF-α levels only increased in the WD group. The ED group exhibited an increase in astrocytic GFAP expression in the hypothalamus and prefrontal cortex but decreases in the hippocampus. Conclusions: These results suggest that UCMS exacerbated the nociceptive response associated with dentin hypersensitivity, concomitant with an increase in plasma corticosterone levels. Hypothalamic and prefrontal cortex astrogliosis in the ED group may be attributable to the increase in corticosterone associated to UCMS procedure. The reduction of astrocytic GFAP expression in the hippocampus in the ED group supports the association between dentin hypersensitivity and depression.

1. Introduction Depression is characterized by alterations in mood and cognitive function and recurrent thoughts of death or suicide, with a lifetime incidence of 15–25% (Paykel, 2006). Depression directly affects not only the patients themselves but also their families and job performance, accounting for a high cost to society (Ustün, Ayuso-Mateos, Chatterji, Mathers, & Murray, 2004). Mood disorders are one of the most common types of mental disorders, approximately 75% of which are depressive disorders, making them a leading cause of disability worldwide (Ferrari et al., 2013; Stovner, Hoff, Svalheim, & Gilhus, 2014). Although depression and pain are common comorbidities, their

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interaction is not fully understood (Shi, Wang, & Luo, 2010). Depression is often associated with a higher incidence of clinical pain complaints. Thus, comorbid pain and depression have been suggested to be a common phenomenon (Bair, Robinson, Katon, & Kroenke, 2003). Animal studies have shown either reduced or enhanced responses in nociceptive tests, depending on the animal model and experimental procedures. Exposure to unpredictable chronic stress has been reported to increase nociceptive thresholds in response to thermal and mechanical stimuli (Pinto-Ribeiro, Almeida, Pêgo, Cerqueira, & Sousa, 2004; Shi, Wang et al., 2010), causes hyperalgesia in response to persistent inflammatory pain (Forbes, Stewart, Matthews, & Reid, 1996), and reduces mechanical allodynia following nerve injury (Shi, Qi, Gao, Wang, & Luo, 2010).

Corresponding author at: Paulista University, Rua Dr. Bacelar, 1212, São Paulo, SP 04026-002, Brazil. E-mail addresses: [email protected], [email protected] (M. Martha Bernardi).

http://dx.doi.org/10.1016/j.archoralbio.2017.04.005 Received 6 January 2017; Received in revised form 2 April 2017; Accepted 7 April 2017 0003-9969/ © 2017 Elsevier Ltd. All rights reserved.

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2.2. Dental erosion and dentin hypersensitivity test

Dentin hypersensitivity is defined as a response to the stimulation of vital dentin that is exposed to thermal, volatile, tactile, osmotic, or chemical stimuli in the oral environment, causing extreme discomfort to the patient. It is characterized by short-term, acute pain of variable intensity (West, Seong, & Davies, 2014). The etiology of dentin hypersensitivity is multifactorial, but the importance of enamel erosion has become more evident (Walters, 2005). Pain may be localized or generalized, affecting the surface of one tooth or many teeth simultaneously, and generally ceases immediately after removal of the stimulus (West et al., 2014). The most widely accepted theory to explain pain that results from dentin hypersensitivity is Hydrodynamic Theory (Brännström, 1963). This theory is based on the movement of dentinal fluid that, in turn, excites mechanoreceptors in the periphery of the pulp. The prevalence, distribution, and presentation of dentin hypersensitivity have been reported in many studies. Differences in these characteristics have been attributed to different patient populations, habits, and diets. Davari et al. (Davari, Ataei, & Assarzadeh, 2013) reported a prevalence of 5–85% in adult populations with non-carious cervical lesions, including erosion lesions, which are among the most common clinical complaints of dental patients. Although some treatments have been suggested in the literature, they are not always sufficient or successful. We sought to investigate possible physical or psychological influences on nociceptive perception. Dentin hypersensitivity can affect the patient’s quality of life and consequently negatively influence dietary and oral health (Davari et al., 2013). We previously showed that treatment with an acidic solution for 30 days caused dentin hypersensitivity after erosive challenge, and severe dentin hypersensitivity was observed after acidic solution treatment for 45 days (Bergamini et al., 2014). Nociceptive behavioral response that was induced by cold stimuli was consistent with the grade of erosion. Additionally, chronic stress plays an important role in dentin hypersensitivity, reflected by an increase in corticosterone levels, a decrease in body weight, and behavioral data (Bergamini et al., 2016). The present study evaluated the nociceptive behavioral response that was induced by dentin hypersensitivity after dental erosion in rats that exhibited depressive-like behavior induced by unpredictable chronic mild stress (UCMS). The UCMS procedure is a classic animal model of depression (D’Aquila, Brain, & Willner, 1994; Forbes et al., 1996; Papp, Willner, & Muscat, 1991). Dentin hypersensitivity was evaluated, and depressive-like parameters were assessed by evaluating sucrose preference and immobility in the forced swim test. We also determined plasma tumor necrosis factor α (TNF-α) and corticosterone levels and astrocytic glial fibrillary acidic protein (GFAP) expression in the prefrontal cortex, hippocampus, amygdala, and hypothalamus.

Erosion was assessed by offering the rats an acid solution (Gatorade®, lemon flavor, pH 2.7) as drinking water for 30 or 45 days. DH test was performed by cold water stimuli (jet of cold water 4 °C, 0.5 ml, assessed by a syringe provided with a metal cannula), applied for 5 s, on the labial surface of molars (the rearmost teeth in the mouth). Three days before the test, the rats were daily habituated to the test manipulation. The animal’s response to nociceptive stimulus was scored (0 = no response; 0.5 = slight contraction of the body; 1 = body contraction; 2 = strong body contraction and a short vocalization; 3 = strong body contraction and a prolonged vocalization). The scores were independently attributed by two observers and the mean score attributed by each one was employed in the DH evaluation. This method was previously validated in our laboratory (Bergamini et al., 2014).

2.3. Unpredictable chronic mild stress procedure The UCMS procedure is used to induce a depressive-like state in rats (D’Aquila et al., 1994; Forbes et al., 1996; Papp et al., 1991). We adapted this method based on Forbes et al. (1996). Briefly, the stressors were unpredictable with regard to their nature, duration, and frequency. The procedure lasted for 30 days and consisted of one different stressor each day. It included 24-h water deprivation, 24-h deprivation of acidic solution or food, 5-min swimming in 4 °C water, heating the paws at 45 °C, restriction of movements and shaking, 5-min stressful handling, exposure to a dirty cage, 1 h ventilation cageless (turn off the ventilation of the cage which increases the smell of the ammonia and other wastes), 1-min tail grip clamp, and 24-h exposure to a wet cage. The stressors were presented in a pseudo-random order. To evaluate depressive-like behavior that was caused by UCMS, the rats were subjected to the Porsolt forced swim test (Porsolt, Anton, Blavet, & Jalfre, 1978) and sucrose preference test (Pollak, Rey, & Monje, 2010).

2.4. Forced swim test The forced swim test is used to evaluate the antidepressant efficacy of drugs and experimental manipulations that seek to cause or prevent depressive-like states (Slattery & Cryan, 2012). Exposure to the swim tank 24 h before the test session is required to discern antidepressant and depressant effects. In the afternoon on the last day of the UCMS procedure, the rats were trained to swim for 10 min in a 20 cm diameter cylindrical tank that was filled with 26 °C water to a depth of 30 cm. The wall of the tank was sufficiently high that the rats could not escape. The next day, the rats were placed again in the tank for a 5 min test session. The latency to immobility and time spent immobile were measured (in seconds).

2. Material and methods 2.1. Animals Thirty-five male Wistar rats, weighing 320–350 g at the beginning of the experiments, were used. The rats were housed in polypropylene cages (38 cm × 32 cm × 16 cm, 5 rats/cage) at a controlled room temperature (22 ± 2 °C) with artificial lighting (12 h/12 h light/dark cycle, lights on at 8 A.M.) with free access to Nuvilab rodent food (Nuvital, São Paulo, Brazil) and filtered water or acidic solution. Sterilized and residue-free wood shavings were used as animal bedding. The experiments began at least 10 days after the rats arrived in the laboratory. The animals were maintained in accordance with the guidelines of the Committee on the Care and Use of Laboratory Animal Resources of Paulista University, São Paulo, Brazil (protocol no. 227/ 14, CEUA/ICS/UNIP). These guidelines conform with those of the National Research Council (Committee, 2011).

2.5. Sucrose preference test Before the UCMS and dental erosion procedures, the animals were trained to consume increasing concentrations of sucrose up to 2%. Baseline sucrose preference over a 48-h period was determined. Afterward, the UCMS procedure was conducted for 4 weeks. Sucrose consumption was evaluated again 48 h after the UCMS procedure was completed. The sucrose preference test was conducted at 9:00 A.M. in the rats’ home cage following 24 h of water deprivation. Two rats per cage were presented simultaneously with two bottles, one that contained 2% sucrose solution and one that contained water. The percentage of sucrose preference was calculated according to the following formula: % sucrose preference = (sucrose solution consumption/[sucrose solution consumption + water consumption]) × 100. 165

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soft tissue. The molars were then isolated for scanning electron microscopy. The specimens were stored in Eppendorf tubes that contained 5% chloramine. The specimens underwent a dehydration process with an ascending series of acetone concentrations (30% for 15 min, 50% for 15 min, 70% for 10 min, 95% for 20 min, 100% for 10 min, and 100% for 20 min). The specimens were then coated with gold palladium at a thickness of ± 15 nm using a Sputter Coater MED020 device (Bal-Tec,LEICA, USA). Afterward, the specimens were observed under a scanning electron microscope (Desk V- Standard, JEOL, USA) at the Dentistry Research Laboratory, Paulista University, to determine correlations between nociceptive behavioral scores and the structural condition of dentin.

2.6. Recording of body weight and acidic solution consumption Body weight was recorded weekly and at the end of the experiments. The acidic solution consumption (ml/bottle) was measured daily and changed for a new solution during the UCMS procedure. 2.7. Immunohistochemistry Distinct alterations in astrocytic plasticity in the central nervous system are associated with depressive disorders (Bowley, Drevets, Öngür, & Price, 2002; Gosselin, Gibney, O’Malley, Dinan, & Cryan, 2009). The expression of GFAP was used as an astrocytic marker to investigate astrocyte plasticity in our UCMS model. All of the rats in the different groups were euthanized by rapid decapitation after the forced swim test. The brains were collected and fixed in 10% buffered formalin for at least 48 h. Three coronal sections from each brain were made, including the prefrontal cortex, limbic structures, and the hypothalamus. The samples were processed according to conventional histological procedures. Each brain section was mounted on silane-treated slides and subjected to GFAP immunohistochemistry using the avidin-biotin peroxidase complex (ABC) method. The immunohistochemical protocol was initiated by paraffin withdrawal of the histological sections in xylene and rehydration in a crescent graded series of ethanol solutions. Antigen retrieval was performed by transferring the slides to 10 mM sodium citrate buffer (pH 6.0) at 95 °C for 20 min. Endogenous peroxidase activity was blocked by 3% hydrogen peroxide for 10 min at room temperature. Two washes with Tris/HCl buffer (pH 6.0, 10× wash buffer, S3006, Dako, Glostrup, Denmark) were performed between incubations. The sections were incubated for 16 h with polyclonal rabbit anti-GFAP immunoglobulin primary antibody (1:1000; Z0334, Dako), followed by incubation with biotinylated secondary antibody (Dako Universal LSAB 2 System-HRP, K0690) according to the manufacturer’s instructions. Immunoreactivity was visualized by incubating the sections in a solution that contained 0.1% diaminobenzidine (K3467, Dako). The sections were then counterstained with Harris’ modified hematoxylin solution, dehydrated, and mounted in Entellan (Merck, Germany). Six photomicrographs of each individual section were taken using a 40× objective. The area of astrocytes and their processes (marked in brown) was automatically calculated (in pixels) using Metamorph software. Calibrations were performed with digital color filters that regulated red, green, and blue bits, such that only positive cell were included and background staining was excluded from the measurements. The area reflected the size and positivity of astrocytic GFAP expression.

2.10. Experimental design Thirty-five adult male rats were divided into four groups. The first group (n = 7) received water during the entire experiment and was not subjected to the UCMS procedure (water and no depression [WND] group). The second group (n = 10) received water during the entire experiment and was subjected to the UCMS procedure (water and depression [WD] group). The third group (n = 8) received the acidic solution for 4 weeks and was not subjected to the UCMS procedure (erosion and no depression [END] group). The fourth group (n = 10) received the acidic solution and was subjected to the UCMS procedure (erosion and depression [ED] group). Before the experiments, the sucrose preference test was performed in all groups to achieve minimal sucrose preference of 75%. Body weight was recorded on the last day of this procedure. At the end of the 4-week experiment, all of the rats were weighed in the morning (8–10 A.M.), and hypersensitivity scores were calculated. The sucrose preference test was conducted between 10 A.M. and 12 P.M., and the forced swim test was performed between 2 P.M. and 5 P.M., followed by euthanasia and blood and organ sample collection. 2.11. Statistical analysis Homogeneity was verified using Bartlett’s test. Normality was verified using the Kolmogorov-Smirnov test. The Kruskal-Wallis test followed by the Dunn’s multiple comparison test was used to analyze dentin hypersensitivity, weight gain and immunohistochemical data. Two-way ANOVA followed by the Bonferroni test was used to analyze plasma TNF-α and corticosterone levels, the latency to immobility and time spent immobile in the forced swim test, and sucrose preference. The results are expressed as mean ± standard error of means (SEM) or medians and 1:99 range. In all cases, the results were considered significant at p < 0.05.

2.8. Plasma TNF-α and corticosterone levels 3. Results At the same time of brain collection, trunk blood was collected in conical tubes that contained 10% ethylenediaminetetraacetic acid. The samples were centrifuged, and plasma was obtained. Plasma samples from each animal were aliquoted in several conical tubes for separate analyses (in duplicate) of TNF-α and corticosterone using commercial enzyme-linked immunosorbent assay kits according to the manufacturer’s instructions. Several findings suggest that UCMS activates the hypothalamic-pituitary-adrenal (HPA) axis and induces immune activation, leading to an increase in plasma TNF-α levels. TNF-α was quantified using the DuoSet R & D Systems kit (catalog no. DY510, Minneapolis, MN, USA). The results are expressed as pg/ml. Corticosterone levels were determined using an Arbor Assays kit (catalog no. K014-H5, Ann Arbor, MI, USA). The results are expressed as ng/ml.

Fig. 1A shows sucrose preference in the WND, WD, END, and ED groups. The two-way ANOVA revealed significant effects of test (F2,38 = 15.73, p < 0.0001) and treatment (F2,38 = 6.24, p < 0.001) and a significant interaction (F2,38 = 37.62, p < 0.0001). Exposure to UCMS reduced sucrose preference in the WD and ED groups in the test session. For weight gain (Fig. 1B), the Kruskal-Wallis revealed significant differences between groups (KW = 19.99). The Dunn’s test revealed a decrease in weight gain in the WD group compared with the WND (p < 0.001), WD (p < 0. 01) and ED (p < 0.01) groups. Acidic solution consumption in each cage of ED group increased compared with the WD group during the UCMS procedure (WD group: 284.50 ± 11.78 ml; ED group: 358.50 ± 9.76 ml; t48 = 4.87, p < 0.0001). For the latency to immobility in the forced swim test (Fig. 1C), the two-way ANOVA revealed a significant difference between depressive and non-depressive rats (F1,29 = 32.21, p < 0.0001) but no effect of

2.9. Scanning electron microscopy After euthanasia, the rats’ jaws were removed and cleaned free of 166

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Fig. 1. Sucrose preference (A), weight gain (B), latency to immobility (C), and time spent immobile (D) in rats subjected or not to UCMS and treated or not with the acidic solution. The WND group (n = 7) received water during the entire experiment and was not subjected to UCMS. The WD group (n = 10) received water during the entire experiment and was subjected to UCMS. The END group (n = 8) received acidic solution for 4 weeks and was not subjected to UCMS. The ED group (n = 10) received the acidic solution for 4 weeks and was subjected to UCMS. For sucrose preference, latency to immobility and time spent immobile, the two way ANOVA followed by the Bonferroni tests were employed. Data of weight gain were analyzed by the Kruskal-Wallis test followed by the Dunn’s multiple-comparison test. .* p < 0.05, **p < 0.01, ***p < 0.0001, compared with WND group; ap < 0.05, compared with WD group.

treatment (F1,29 = 0.05, p = 0.82) and no interaction between factors (F1,29 = 0.96). The Bonferroni test showed that the WD and ED groups exhibited a decrease in the latency to immobility compared with the WND and END groups, respectively. For the time spent immobile (Fig. 1D), the two-way ANOVA revealed a significant difference between depressive and non-depressive rats (F1,29 = 95.48, p < 0.0001) but no effect of treatment (F1,29 = 3.48, p = 0.07) and no interaction between factors (F1,29 = 0.3). The Bonferroni test showed that the WD and ED groups exhibited an increase in the time spent immobile compared with the WND and END groups, respectively. The median hypersensitivity score for each rat scored independently by both observers shows an agreement of 0.98, thus validating our method. For dentin hypersensitivity (Fig. 2), the Kruskal-Wallis test revealed differences between groups (KW = 16.03). Dunn’s multiplecomparison test showed that dentin hypersensitivity scores increased in the ED group (p < 0.01) and END (p < 0.05) groups compared with the WND and WD groups. The scanning electron microscopy images showed open tubules in the groups with dental erosion, which was compatible with the degree of nociceptive behavioral response. The WND presented a smear layer without tubule exposion (Fig. 3). For plasma corticosterone levels (Fig. 4A), the ANOVA revealed significant effects of treatment (F1,31 = 26.06, p = 0.0001) and UCMS (F1,31 = 7.94, p = 0.008) but no treatment × UCMS interaction (F1,31 = 0.32, p = 0.58). The Bonferroni test showed an increase in plasma corticosterone levels in the WD group compared with the WND group (p < 0.05). Treatment with acidic solution and the UCMS procedure in the ED group potentiated the increase in plasma corticos-

Fig. 2. Dentin hypersensitivity scores in rats treated or not with the acidic solution and subjected or not to the UCMS procedure. See Fig. 1 for descriptions of the different groups. Data are presented as medians (min-max) were the lines within the boxes represent median values. The Kruskal-Wallis test followed by the Dunn’s multiplecomparison test were used to analyze data. *p < 0.05, **p < 0.01, compared with WND and WD groups, respectively.

terone levels compared with the END group (p < 0.0001). For plasma TNF-α levels (Fig. 4B), the two-way ANOVA revealed significant interaction between treatment × UCMS (F1,31 = 4.38, p = 0.04) but no effect of treatment (F1,31 = 0, p = 0.97) or UCMS 167

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Fig. 3. Scanning electron microscope images of the molar occlusal surface in the WND, WD, END, and ED groups. See Fig. 1 for descriptions of the different groups.

4.1. About body weight and corticosterone plasmatic levels

(F1,31 = 0.70, p = 0.41). The Bonferroni test indicated a decreased TNF-alpha levels of ED group relative to WD group (p < 0.05). For the area of GFAP-positive astrocytes in the prefrontal cortex (Fig. 5A), the ANOVA revealed significant effects of dentin hypersensitivity (F1,112 = 3067.58, p < 0.0001) and UCMS (F1,112 = 8074.11, p < 0.0001) and a significant dentin hypersensitivity × UCMS interaction (F1,112 = 9169.67, p < 0.0001). The Bonferroni test showed an increase in the area of GFAP-positive astrocytes in the WD, END, and ED groups compared with the WND group. For the area of GFAP-positive astrocytes in the hippocampus (Fig. 5B), the ANOVA revealed significant effects of dentin hypersensitivity (F1,27 = 89.22, p < 0.0001) and UCMS (F1,27 = 42.59, p < 0.0001) and a significant dentin hypersensitivity × UCMS interaction (F1,27 = 85.72, p < 0.0001). The Bonferroni test showed a decrease in the area of GFAP-positive astrocytes in the ED group compared with the END group. For the area of GFAP-positive astrocytes in the amygdala (Fig. 5C), the ANOVA revealed no effects of dentin hypersensitivity (F1,56 = 0.49, p = 0.48) or UCMS (F1,56 = 3.75, p = 0.06) and no dentin hypersensitivity × UCMS interaction (F1,56 = 0.12, p < 0.73). For the area of GFAP-positive astrocytes in the hypothalamus (Fig. 5D), the ANOVA revealed a significant effect of dentin hypersensitivity (F1,60 = 9.05, p = 0.004), no effect of UCMS (F1,60 = 0.09, p = 0.76), and no dentin hypersensitivity × UCMS interaction (F1,60 = 0.16, p = 0.69). The Bonferroni test showed an increase in the area of GFAP-positive astrocytes in the ED group compared with the END group. Fig. 6 shows immunohistochemical GFAP expression in the prefrontal cortex, hippocampus, amygdala, and hypothalamus.

A decrease in body weight gain and increase in plasma corticosterone levels were observed in rats in the WD group compared with controls. A decrease in weight gain (Bielajew, Konkle, & Merali, 2002; Willner, Towell, Sampson, Sophokleous, & Muscat, 1987) and increase in plasma corticosterone levels (Grippo et al., 2005) are phenotypes of depression that have been reported after chronic stress. This reduction of weight gain unlikely resulted from anhedonia because measures of anhedonia with palatable solutions are independent of weight gain. However, Karagiannides et al. (2014) showed that stressed rats showed no weight gain compared to control animals. Cox et al. (Cox, Alsawah, McNeill, Galloway, & Perrine, 2011) reported only an attenuation of body weight gain during stress exposure. Thus, conflicting data on body weight gain have been reported during exposure to UCMS. In the present study, the WD group exhibited a decrease in body weight gain compared with non-UCMS-exposed rats, together with an increase in plasma corticosterone levels. These conflicting results may be attributable to methodological differences between these studies. No reduction of body weight gain was observed in the ED group compared with non-UCMS-exposed rats. The acidic solution that was used in the present study has 48 kcal and 12 g of carbohydrates per 200 ml volume. Compared with the WD group, body weight during treatment significantly increased in the ED group, which likely compensated for the weight loss that was induced by UCMS, despite the elevated levels of corticosterone.

4.2. About dentin hypersensitivity Rats that were treated with acidic solution for 30 days exhibited an increase in dentin hypersensitivity (Bergamini et al., 2014), and restraint stress plus shaking potentiated dentin hypersensitivity (Bergamini et al., 2016). Similar results were observed in the present study. Rats that were subjected to UCMS and received the acidic solution (ED group) exhibited an increase in dentin hypersensitivity compared with rats that were not subjected to UCMS but received the acidic solution (END group). Both the ED and END groups had higher dentin hypersensitivity scores than controls and rats that were not treated with the acidic solution (WD and WND groups).

4. Discussion In the present study, the UCMS procedure induced depression-like behavior in the WD group, revealed by a decrease in sucrose preference, a decrease in the latency to immobility, and an increase in the time spent immobile in the forced swim test. Rats that were subjected to UCMS and treated with the acidic solution (ED group) exhibited depressive-like behavior in both the sucrose preference test and forced swim test at levels similar to the WD group. 168

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greatest risk factor is chronic stress (Fasick, Spengler, Samankan, Nader, & Ignatowski, 2015). Chronic stress is a major risk factor that predisposes individuals to the development of depression (BlackburnMunro & Blackburn-Munro, 2001; Hart, Martelli, & Zasler, 2000). Stress is associated with dysregulation of the HPA axis (Selye, 1998), activation of the immune system Covey, Ignatowski, Knight, & Spengler, 2000), and heightened sympathetic nervous system tone (Schlereth & Birklein, 2008). Patients with depressive illness frequently present depression-related abnormalities of the HPA axis, which may include an increase in glucocorticoid production in the adrenal glands and/or an increase in corticotrophin-releasing factor production in the hypothalamus (Holsboer, 2000; Maletic et al., 2007; Mizoguchi, Shoji, Ikeda, Tanaka, & Tabira, 2008; Urani & Gass, 2003). In the present study, rats in both groups exposed to UCMS procedure exhibited an increase in plasma corticosterone levels, consistent with a previous report (Bergamini et al., 2014). Corticosterone levels were measured because stress disrupts the control of glucocorticoid release at various points along the HPA axis (Munck, Guyre, & Holbrook, 1984), similar to the human cortisol response (Römer et al., 2009). We observed that the levels of corticosterone levels in rats exposed to UCMS plus dentin erosion (ED group) was potentiated relative to WD group suggesting that dentin hypersensitivity induces additional stress. 4.3. About TNF-α levels and astrocytic GFAP expression Analyses of plasma TNF-α levels and astrocytic GFAP expression in the prefrontal cortex, hypothalamus, amygdala, and hippocampus by immunohistochemistry were performed because both depression and the UCMS model are related to peripheral and central nervous system inflammatory processes (Bakunina, Pariante, & Zunszain, 2015; Demirtaş et al., 2014; Farooq et al., 2012; Gosselin et al., 2009; Hamidi, Drevets, & Price, 2004; Maes et al., 2012; Ye, Wang, Wang, & Wang, 2011). Data about peripheral cytokines as TNF-α in rats exposed to UCMS procedure are contradictory. Diverse theories have been generated to explain the etiology of depression, and frequently observed co-occurrence of depressive disorders and inflammatory diseases suggests a close connection between the nervous and the immune systems. Recently, several data have demonstrated a strong correlation between cytokines and the pathology of depression (Bremmer et al., 2008). Under physiological conditions, cytokines are key regulatory mediators involved in the host response to immunological challenges and play a critical role in the communication between the endocrine, immune, and central nervous systems (Alves & Palermo-Neto, 2007). However, constant activation of inflammatory pathways with an overproduction of pro-inflammatory cytokines can detrimentally affect neuroendocrine processes, causing hyperactivity of the HPA axis and impairing the ability of nervous system to respond and adapt to external or internal stimuli (Dantzer, O’Connor, Freund, Johnson, & Kelley, 2008). Dantzer, Wollman, Vitkovic, and Yirmiya (1999) proposed the “cytokine hypothesis of depression,” which postulates that proinflammatory cytokines are key factors in mediating behavioral, neuroendocrine, and neurochemical features of depressive disorders. Patients with depression frequently present alterations of the immune system, such as elevated proinflammatory cytokine levels in plasma and cerebrospinal fluid (Miller, Maletic, & Raison, 2009). Depression is often associated with HPA axis hyperactivity, which is characterized by hypercortisolemia. Hyperactivity of the HPA axis may normally be prevented by means of an inhibitory feedback mechanism, and dysregulation of this feedback mechanism appears to occur in depressive disorders (Young, Haskett, Murphy-Weinberg, Watson, & Akil, 1991). Proinflammatory cytokines are potent activators of the HPA axis (Dunn, 2000) and play a critical role in activating the HPA axis in major depression. In the present study, both groups exposed to UCMS (WD and ED groups) showed increased in plasma corticosterone levels as expected in rats exposed to chronic stress. However only rats of WD group showed

Fig. 4. Plasma corticosterone (A) and TNF-α (B) levels in rats treated or not with the acidic solution 4 weeks and subjected or not to the UCMS procedure. See Fig. 1 for descriptions of the different groups. To corticosterone levels *p < 0.05 compared to WND group and ***p < 0.001 compared with END groups. To TNF-α *P < 0.05 relative to ED group (two-way ANOVA followed by Bonferroni test).

Increases in chronic pain sensitivity have been reported in depression patients (Adler & Gattaz, 1993; Bair et al., 2003; Strigo, Simmons, Matthews, Craig, & Paulus, 2008) and animal models of depression (Shi et al., 2010; Zhang et al., 2013 Zhang et al., 2013). Pain and depression share common neuroanatomical pathways and neurobiological substrates, which might explain the higher vulnerability to pain in depression patients and higher vulnerability to depression in individuals who experience chronic pain (Ohayon & Schatzberg, 2003). Depression patients present increases in pain thresholds in response to pressure and cold stimuli and a decrease in pain thresholds in response to high-frequency electrical stimulation of the skin (Adler & Gattaz, 1993; Lautenbacher, Spernal, Schreiber, & Krieg, 1999; Strigo et al., 2008). However, other studies of depression patients reported a decrease in responsiveness to evoked pain (Merskey, 1965; Moroz, Nuller, Ustimova, & Andreev, 1990). These contradictory results could be attributable to the type and frequency of the noxious stimulus. The dysregulation of central monoaminergic function has been observed In depressive illness (Delgado, 2000; Elhwuegi, 2004), which may cause or enhance the nociceptive perception in rats (Burke et al., 2010). Modulating brain monoamine levels may simultaneously relieve depressive symptoms and facilitate the descending inhibitory pain pathways, thereby inducing analgesia. However, depression is mediated by a combination of genetic, biochemical, socioeconomic, psychological, environmental, and life-experience factors, and the

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Fig. 5. Area of GFAP positivity in the prefrontal cortex (A), hippocampus (B), amygdala (C), and hypothalamus (D) in rats treated or not with the acidic solution for 4 weeks and subjected or not to the UCMS procedure. See Fig. 1 for descriptions of the different groups. To prefrontal cortex- **p < 0.01, *** p < 0.001 relative to WND, ***p < 0.001 relative to END group. To hippocampus- ***p < 0.001 relative to END group. To hypothalamus -* p < 0.05 relative to END group. (two-way ANOVA followed by Bonferroni test).

attenuate the systemic inflammatory response partly by altering cytokine expression. Antecedent glucocorticoid administration by 6 h in human endotoxemia also increases IL-10 release, a antiinflammatory cytokine, above the IL-10 response mounted to endotoxin alone. Thus, we hypothesized that the lack of increases in peripheral TNF-alpha levels in rats submitted to UCMS resulted by the heightened corticosterone levels previously released by the UCMS exposure plus dentin hypersensitivity. Concerning to UCMS procedure model and pro-inflammatory cytokines, an absence of peripheral cytokine alteration was observed by Farooq et al. (2012) in mice. Furthermore, other studies using UCMS (d’Audiffret et al., 2010), social stress as well as intraperitoneal LPS injection have also reported an absence of cytokine alterations (Gibb, Hayley, Poulter, & Anisman, 2011). In this respect, apart LPS inducing an acute inflammatory stimulus (Reddy Metukuri, Reddy, Reddy, & Reddanna, 2010), it is itself known to induce a syndrome of behavioral sickness which is considered as a model of depression (Song & Wang, 2011). Similar as observed by Farooq et al. (2012), besides the lack of effects in peripheral levels of TNF-α in ED group,we observed increased neuroinflammation in prefrontal area of WD, END and ED groups relative to WND group. Also, in the hypothalamus of ED group the area of GFAP expression was increased relative to END group. Concerning the hippocampus the ED group showed reduced in the area of GFAP expression. No differences were observed between groups in the amygdale. A growing body of evidence suggests that glial cells are involved in practically all aspects of neural function. Glial cells regulate homeostasis in the brain, influence the development of the nervous system, modulate synaptic activity, and carry out the immune response inside the brain (Purves et al., 2001). Glial cells also play an important role in

increase in TNF-α levels compared to WND group while the ED group shows decreased in this cytokine. Concerning these apparently controversial data, it is important to focus on the role of cytokines in inflammatory and body injuries.Cytokines bind to specific cellular receptors that result in activation of intracellular signaling pathways that regulate gene transcription. By this mechanism, cytokines influence immune cell activity, differentiation, proliferation, and survival. These mediators also regulate the production and activity of other cytokines, which may either augment (proinflammatory) or attenuate (antiinflammatory) the inflammatory response (Lin, Calvano, & Lowry, 2000). The cytokine cascade activated in response to injury consists of a complex biochemical network with diverse effects on the injured host (Martich, Boujoukos, & Suffredini, 1993). After acute injury or during infections, TNF-α, a pro-inflammatory cytokine, is among the earliest and most potent mediators of subsequent host responses. Although the half-life of TNF-α is less than 20 min, this brief appearance is sufficient to evoke marked metabolic and hemodynamic changes and activate mediators distally in the cytokine cascade. Other functions of TNF-α include activation of coagulation, promoting the expression or release of adhesion molecules, prostaglandin E2, platelet-activating factor (PAF), glucocorticoids, and eicosanoids (Feghali & Wright, 1997). Cortisol and glucocorticoids regulates cytokine activity. The hormonal responses mounted by the injured host or the antecedent hormonal milieu of the cell have considerable influence on the inflammatory cytokine response. The anti-inflammatory effects of glucocorticoids include decreased TNF-α and IL-1 transcription, inducible cyclooxygenase-2 (COX-2) generation, and adhesion molecule expression (Wissink, van Heerde, van der Burg, & van der Saag, 1998). In healthy human subjects, glucocorticoid administration immediately before or concomitantly with endotoxin infusion is able to 170

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Fig. 6. Immunohistochemical GFAP expression in the prefrontal cortex, hippocampus, amygdala, and hypothalamus of WND (a), WD (b), END (c), and ED (d) groups. See Fig. 1 for descriptions of the different groups.

structural modifications in different cortical regions, including the amygdala, anterior cingulate cortex, hippocampus and prefrontal cortex (Kim & Kim, 2016; Lithwick, Lev, & Binshtok, 2013). In addition, chronic stress is also positively correlated with increases in microglial and long-term neuronal activation in the prefrontal cortex (DiasFerreira et al., 2009; Hinwood, Morandini, Day, & Walker, 2012). Thus, we propose that, both UCMS procedure and dentin hypersensitivity, induced in prefrontal cortex neuroinflammation. Moreover we observed an interaction between UCMS procedure and dentin hypersensitivity in astrogliosis of ED group. Glia have been shown to be involved in the neuropathology of mood disorders (Bowley et al., 2002; Cotter, Mackay, Landau, Kerwin, & Everall, 2001; Miguel-Hidalgo et al., 2000; Sanacora & Banasr, 2013). Chronic exposure to glucocorticoids is neurotoxic, and hippocampal granule cells are particularly sensitive to these effects, leading to a loss of the inhibitory effect of the hippocampus on HPA axis. First, the UCMS exposure induces an initial activation of microglia in the hippocampus, probably driven by increased exposure to glucocorticoids (Walker, Nilsson, & Jones, 2013): More prolonged exposure to UCMS causes a decreased hippocampal expression of the nuclear transcription CREB (factor cAMP response element-binding), leading to decreased expression of BDNF (brain-derived neurotrophic factor) and other neurotrophins (Willner, 2016). This loss of trophic support to neuronal structure and function results in shrinkage of the dendritic tree of hippocampal neurons (Bessa et al., 2009), and resulted in loss of granule cells (Jayatissa, Henningsen, Nikolajsen, West, & Wiborg, 2010). Moreover, the hippocampus is one of very few brain areas in which neurogenesis continues

restoring the nervous system after neural damage, and they also participate in various neurodegenerative disorders (Barres, 2008). Astrocytes are dynamic cells that respond to changes in the central nervous system (CNS) by undergoing morphological and functional alterations that affect neuronal activity (García-Cáceres, Yi, & Tschöp, 2013). In response to CNS insults, astrocytes develop a hypertrophic or reactive phenotype termed astrogliosis (Levine, Kong, Nadler, & Xu, 1999), which is characterized by the upregulation of specific structural proteins, such as glial fibrillary acidic protein (GFAP) and vimentin (Ridet et al., 1996). In the central nervous system, glial cells, namely microglia and astrocytes, are involved in both chronic pain and depression (Jo, Zhang, Emrich, & Dietrich, 2015). Distinct alterations of astrocyte plasticity in the central nervous system are associated with depressive disorders (Bowley et al., 2002; Gosselin et al., 2009; Ye et al., 2011). Therefore, GFAP was used as an astrocytic marker to investigate astrocyte behavior in our model of UCMS. UCMS increased the area of GFAP positivity in the prefrontal cortex of WD group but not in the hypothalamus, amygdale and hippocampus, suggesting the presence of neuroinflammation in prefrontal cortex. Also, astrogliosis was observed in END and ED groups. The frontal cortex in association with the parietal cortex, basal ganglia, thalamus and cerebellum are involved in high-level cognitive functions such as working memory, set shifting, fluency, focused attention, episodic memory retrieval, abstract thinking, tracking alternative outcomes during decision-making and planning (Rabinovici, Stephens, & Possin, 2015). Recent experiments conducted in both human patients and animal models have demonstrated that the presence of chronic pain is closely associated with significant functional and

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Results from a population-based study. Journal of Affective Disorders, 106(3), 249–255. http://dx.doi.org/10.1016/j.jad.2007.07.002. Burke, N. N., Hayes, E., Calpin, P., Kerr, D. M., Moriarty, O., Finn, D. P., & Roche, M. (2010). Enhanced nociceptive responding in two rat models of depression is associated with alterations in monoamine levels in discrete brain regions. Neuroscience, 171(4), 1300–1313. http://dx.doi.org/10.1016/j.neuroscience.2010. 10.030. Committee (2011). Guide for the care and use of laboratory animals: Eighth edition. http:// dx.doi.org/10.2307/1525495. Cotter, D., Mackay, D., Landau, S., Kerwin, R., & Everall, I. (2001). Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Archives of General Psychiatry, 58(6), 545–553 http://doi.org/yoa9460 [pii]. Covey, W. C., Ignatowski, T. A., Knight, P. R., & Spengler, R. N. (2000). Brain-derived TNFalpha: Involvement in neuroplastic changes implicated in the conscious perception of persistent pain. Brain Research, 859(1), 113–122. http://dx.doi.org/10. 1016/S0006-8993(00)01965-X. Cox, B. M., Alsawah, F., McNeill, P. C., Galloway, M. P., & Perrine, S. A. (2011). Neurochemical, hormonal, and behavioral effects of chronic unpredictable stress in the rat. Behavioural Brain Research, 220(1), 106–111. http://dx.doi.org/10.1016/j. bbr.2011.01.038. D’Aquila, P. S., Brain, P., & Willner, P. (1994). Effects of chronic mild stress on performance in Behavioural tests relevant to anxiety and depression. Physiology and Behavior, 56(5), 861–867. http://dx.doi.org/10.1016/0031-9384(94)90316-6. Dantzer, R., Wollman, E., Vitkovic, L., & Yirmiya, R. (1999). Cytokines and depression: Fortuitous or causative association? Molecular Psychiatry, 4(4), 328–332. http://dx. doi.org/10.1038/sj.mp.4000572. Dantzer, R., O’Connor, J., Freund, G., Johnson, R., & Kelley, K. (2008). From inflammation to sickness and depression: When the immune system subjugates the brain. Nature Reviews Neuroscience, 9(1), 46–56. http://dx.doi.org/10.1038/nrn2297. Davari, A., Ataei, E., & Assarzadeh, H. (2013). Dentin hypersensitivity: Etiology, diagnosis and treatment; A literature review. Journal of Dentistry (Shiraz, Iran), 14(3), 136–145. Retrieved from http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=3927677&tool=pmcentrez&rendertype=abstract. Delgado, P. L. (2000). Depression: The case for a monoamine deficiency. Journal of Clinical Psychiatry, 61, 7–11. Demirtaş, T., Utkan, T., Karson, A., Yazır, Y., Bayramgürler, D., & Gacar, N. (2014). The link between unpredictable chronic mild stress model for depression and vascular inflammation? Inflammation, 37(5), 1432–1438. http://doi.org/10.1007/s10753014-9867-4. Dias-Ferreira, E., Sousa, J. C., Melo, I., Morgado, P., Mesquita, A. R., Cerqueira, J. J., ... Koob, G. F. (2009). Chronic stress causes frontostriatal reorganization and affects decision-making. Science (New York, N.Y.), 325(5940), 621–625. http://dx.doi.org/ 10.1126/science.1171203. Dunn, A. J. (2000). Cytokine activation of the HPA axis. Annals of the New York Academy of Sciences, 917(1), 608–617. http://dx.doi.org/10.1111/j.1749-6632.2000. tb05426.x. Elhwuegi, A. S. (2004). Central monoamines and their role in major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 28(3), 435–451. http://doi. org/10.1016/j.pnpbp.2003.11.018. Farooq, R. K., Isingrini, E., Tanti, A., Le Guisquet, A. M., Arlicot, N., Minier, F., ... Camus, V. (2012). Is unpredictable chronic mild stress (UCMS) a reliable model to study depression-induced neuroinflammation? Behavioural Brain Research, 231(1), 130–137. http://dx.doi.org/10.1016/j.bbr.2012.03.020. Fasick, V., Spengler, R., Samankan, S., Nader, N., & Ignatowski, T. (2015). The hippocampus and TNF: Common links between chronic pain and depression. Neuroscience and Biobehavioral Reviews, 53, 139–159. http://dx.doi.org/10.1016/j. neubiorev.2015.03.014. Feghali, C. A., & Wright, T. M. (1997). Cytokines in acute and chronic inflammation. Frontiers in Bioscience: A Journal and Virtual Library, 2, d12–d26. Ferrari, A. J., Charlson, F. J., Norman, R. E., Patten, S. B., Freedman, G., Murray, C. J. L., ... Whiteford, H. A. (2013). Burden of depressive disorders by country, sex, age, and year: Findings from the Global Burden of Disease Study 2010. PLoS Medicine, 10(11), http://dx.doi.org/10.1371/journal.pmed.1001547. Forbes, N. F., Stewart, C. A., Matthews, K., & Reid, I. C. (1996). Chronic mild stress and sucrose consumption: Validity as a model of depression. Physiology and Behavior, 60(6), 1481–1484. http://dx.doi.org/10.1016/S0031-9384(96)00305-8. García-Cáceres, C., Yi, C. X., & Tschöp, M. H. (2013). Hypothalamic astrocytes in obesity. Endocrinology and Metabolism Clinics of North America, 42(1), 57–66. http://doi.org/ 10.1016/j.ecl.2012.11.003. Gibb, J., Hayley, S., Poulter, M. O., & Anisman, H. (2011). Effects of stressors and immune activating agents on peripheral and central cytokines in mouse strains that differ in stressor responsivity. Brain, Behavior, and Immunity, 25(3), 468–482. http://dx.doi. org/10.1016/j.bbi.2010.11.008. Gosselin, R.-D., Gibney, S., O’Malley, D., Dinan, T. G., & Cryan, J. F. (2009). Region specific decrease in glial fibrillary acidic protein immunoreactivity in the brain of a rat model of depression. Neuroscience, 159(2), 915–925. http://dx.doi.org/10.1016/j. neuroscience.2008.10.018. Grippo, A. J., Sullivan, N. R., Damjanoska, K. J., Crane, J. W., Carrasco, G. A., Shi, J., ... Van De Kar, L. D. (2005). Chronic mild stress induces behavioral and physiological changes, and may alter serotonin 1A receptor function, in male and cycling female rats. Psychopharmacology, 179(4), 769–780. http://dx.doi.org/10.1007/s00213-0042103-4. Hamidi, M., Drevets, W., & Price, J. (2004). Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biological Psychiatry, 55(6), 563–569. http://dx.doi.org/10.1016/j.biopsych.2003.11.006. Hart, R. P., Martelli, M. F., & Zasler, N. D. (2000). Chronic pain and neuropsychological

into adult life. This process is powerfully suppressed by prolonged exposure to corticosterone or to stressors (Petrik, Lagace, & Eisch, 2012), as here observed. These morphological changes are associated with a decrease in the volume of the hippocampus following UCMS (Y Palacios et al., 2011). In the present study we suggest that the decreased hippocampal area of GFAP expression observed in the ED group resulted of the high levels of corticosterone induced by the dentin hypersensitivity associated to UCMS procedure. The astrogliosis observed in the hypothalamus only in ED group corroborates with this hypothesis. 5. Conclusions The UCMS procedure potentiated the nociceptive behavioral response associated with dentin hypersensitivity caused by dental erosion, concomitant with an increase in plasma corticosterone levels. Association between UCMS procedure and dentin hypersensitivity induces neuroinflammation in the frontal cortex and hypothalamus and decreased hippocampal area of GFAP expression, which is the major abnormality reported in structural imaging studies of patients with depression. Conflicts of interest None. Acknowledgement This study is part of Fabiane Martins Barbosa Master thesis presented to the Graduate Program in Dentistry, Paulista University, Rua Dr. Bacelar, 1212, São Paulo, SP 04026-002, Brazil. References Adler, G., & Gattaz, W. F. (1993). Pain perception threshold in major depression. Biological Psychiatry, 34(10), 687–689. http://dx.doi.org/10.1016/0006-3223(93) 90041-B. Alves, G. J., & Palermo-Neto, J. (2007). Neuroimmunomodulation: The cross-talk between nervous and immune systems. Revista brasileira de Psiquiatria, 29(4), 363–369. http://dx.doi.org/10.1590/S1516-44462006005000052. Bair, M. J., Robinson, R. L., Katon, W., & Kroenke, K. (2003). Depression and pain comorbidity: A literature review. Archives of Internal Medicine, 163(20), 2433–2445. http://dx.doi.org/10.1001/archinte.163.20.2433. Bakunina, N., Pariante, C., & Zunszain, P. (2015). Immune mechanisms linked to depression via oxidative stress and neuroprogression. Immunology, 144(3), 365–373. http://doi.org/10.1111/imm.12443. Barres, B. (2008). The mystery and magic of Glia: A perspective on their roles in health and disease. Neuron, 60(3), 430–440. http://dx.doi.org/10.1016/j.neuron.2008.10. 013. Bergamini, M. R., Bernardi, M. M., Sufredini, I., Ciaramicoli, M., Kodama, R., Kabadayan, F., & Saraceni, C. C. (2014). Dentin hypersensitivity induces anxiety and increases corticosterone serum levels in rats. Life Sciences, 98(2), 96–102. http://dx.doi.org/10. 1016/j.lfs.2014.01.004. Bergamini, M., Kabadayan, F., Bernardi, M., Suffredini, I., Ciaramicoli, M., Kodama, R., & Saraceni, C. (2016). Stress and its role in the dentin hypersensitivity in rats. Archives of Oral Biology, 73, 151–160. http://dx.doi.org/10.1016/j.archoralbio.2016.10.007. Bessa, J. M., Ferreira, D., Melo, I., Marques, F., Cerqueira, J. J., Palha, J. A., ... Sousa, N. (2009). The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Molecular Psychiatry, 14(8), 764–773. http://dx.doi.org/10.1038/mp.2008.119 739. Bielajew, C., Konkle, A. T. M., & Merali, Z. (2002). The effects of chronic mild stress on male Sprague-Dawley and Long Evans rats: I. Biochemical and physiological analyses. Behavioural Brain Research, 136(2), 583–592. http://dx.doi.org/10.1016/S01664328(02)00222-X. Blackburn-Munro, G., & Blackburn-Munro, R. E. (2001). Chronic pain, chronic stress and depression: Coincidence or consequence? Journal of Neuroendocrinology, 13, 1009–1023. http://doi.org/10.1046/j.0007-1331.2001.00727.x. Bowley, M. P., Drevets, W. C., Öngür, D., & Price, J. L. (2002). Low glial numbers in the amygdala in major depressive disorder. Biological Psychiatry, 52(5), 404–412. http:// dx.doi.org/10.1016/S0006-3223(02)01404-X. Brännström, M. (1963). A hydrodynamic mechanism in the transmission of painproduced stimuli through the dentine. In D. Anderson (Ed.), Sensory mechanisms in dentine (pp. 73–79). Oxford: Pergamon. Bremmer, M. A., Beekman, A. T. F., Deeg, D. J. H., Penninx, B. W. J. H., Dik, M. G., Hack, C. E., & Hoogendijk, W. J. G. (2008). Inflammatory markers in late-life depression:

172

Archives of Oral Biology 80 (2017) 164–174

F.M. Barbosa et al.

unpredictable stress inhibits nociception in male rats. Neuroscience Letters, 359(1–2), 73–76. http://dx.doi.org/10.1016/j.neulet.2004.02.016. Pollak, D. D., Rey, C. E., & Monje, F. J. (2010). Rodent models in depression research: Classical strategies and new directions. Annals of Medicine, 42(4), 252–264. http://dx. doi.org/10.3109/07853891003769957. Porsolt, R. D., Anton, G., Blavet, N., & Jalfre, M. (1978). Behavioural despair in rats: A new model sensitive to antidepressant treatments. European Journal of Pharmacology, 47, 379–391. http://dx.doi.org/10.1016/0014-2999(78)90118-8. Purves, D., Augustine, G., Fitzpatrick, D., Katz, L., LaMantia, A.-S., McNamara, J., & Williams, M. (2001). Neuroscience(2nd ed.). . Römer, B., Lewicka, S., Kopf, D., Lederbogen, F., Hamann, B., Gilles, M., ... Deuschle, M. (2009). Cortisol metabolism in depressed patients and healthy controls. Neuroendocrinology, 90(3), 301–306. http://dx.doi.org/10.1159/000235904. Rabinovici, G. D., Stephens, M. L., & Possin, K. L. (2015). Executive dysfunction. Behavioral Neurology and Neuropsychiatry, 21(3), 646–659. http://dx.doi.org/10. 1212/01.CON.0000466658.05156.54 Continuum (Minneapolis, Minn.). Reddy Metukuri, M., Reddy, C. M. T., Reddy, P. R. K., & Reddanna, P. (2010). Bacterial LPS mediated acute inflammation-induced spermatogenic failure in rats: Role of stress response proteins and mitochondrial dysfunction. Inflammation, 33(4), 235–243. http://dx.doi.org/10.1007/s10753-009-9177-4. Ridet, J. L., Alonso, G., Chauvet, N., Chapron, J., Koenig, J., & Privat, A. (1996). Immunocytochemical characterization of a new marker of fibrous and reactive astrocytes. Cell and Tissue Research, 283(1), 39–49. http://dx.doi.org/10.1007/ s004410050510. Sanacora, G., & Banasr, M. (2013). From pathophysiology to novel antidepressant drugs: Glial contributions to the pathology and treatment of mood disorders. Biological Psychiatry, 73(12), 1172–1179. http://doi.org/10.1016/j.biopsych.2013.03.032. Schlereth, T., & Birklein, F. (2008). The sympathetic nervous system and pain. NeuroMolecular Medicine, 10(3), 141–147. http://dx.doi.org/10.1007/s12017-0078018-6. Selye, H. (1998). A syndrome produced by diverse nocuous agents. 1936. The Journal of Neuropsychiatry and Clinical Neurosciences, 10(2), 230–231. http://dx.doi.org/10. 1038/138032a0. Shi, M., Qi, W. J., Gao, G., Wang, J. Y., & Luo, F. (2010). Increased thermal and mechanical nociceptive thresholds in rats with depressive-like behaviors. Brain Research, 1353, 225–233. http://dx.doi.org/10.1016/j.brainres.2010.07.023. Shi, M., Wang, J., & Luo, F. (2010). Depression shows divergent effects on evoked and spontaneous pain behaviors in rats. Journal of Pain, 11(3), 219–229. http://dx.doi. org/10.1016/j.jpain.2009.07.002. Slattery, D., & Cryan, J. F. (2012). Using the rat forced swim test to assess antidepressantlike activity in rodents. Nature Protocols, 7(6), 1009–1014. http://dx.doi.org/10. 1038/nprot.2012.044. Song, C., & Wang, H. (2011). Cytokines mediated inflammation and decreased neurogenesis in animal models of depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 35(3), 760–768. http://doi.org/10.1016/j.pnpbp.2010.06. 020. Stovner, L. J., Hoff, J. M., Svalheim, S., & Gilhus, N. E. (2014). Neurological disorders in the global burden of disease 2010 study. Acta Neurologica Scandinavica, 129(S198), 1–6. http://dx.doi.org/10.1111/ane.12229. Strigo, I. A., Simmons, A. N., Matthews, S. C., Craig, A. D. B., & Paulus, M. P. (2008). Association of major depressive disorder with altered functional brain response during anticipation and processing of heat pain. Archives of General Psychiatry, 65(11), 1275–1284. http://dx.doi.org/10.1001/archpsyc.65.11.1275. Urani, A., & Gass, P. (2003). Corticosteroid receptor transgenic mice: Models for depression? Annals of the New York Academy of Sciences, 1007, 379–393. http://dx. doi.org/10.1196/annals.1286.037. Ustün, T. B., Ayuso-Mateos, J. L., Chatterji, S., Mathers, C., & Murray, C. J. L. (2004). Global burden of depressive disorders in theyear 2000. The British Journal of Psychiatry: The Journal of Mental Science, 184, 386–392. http://dx.doi.org/10.1192/ bjp.184.5.386. Walker, F. R., Nilsson, M., & Jones, K. (2013). Acute and chronic stress-induced disturbances of microglial plasticity, phenotype and function. Current Drug Targets, 14, 1262–1276. http://dx.doi.org/10.2174/13894501113149990208. Walters, P. A. (2005). Dentinal hypersensitivity: A review. Journal of Contemporary Dental Practice, 6(2), 107–117. [pii]. http://doi.org/1526-3711-229. West, N., Seong, J., & Davies, M. (2014). Dentine hypersensitivity. Monographs in Oral Science, 25, 108–122. http://dx.doi.org/10.1159/000360749. Willner, P., Towell, A., Sampson, D., Sophokleous, S., & Muscat, R. (1987). Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology, 93(3), 358–364. http://dx.doi.org/10. 1007/BF00187257. Willner, P. (2016). The chronic mild stress (CMS) model of depression: History, evaluation and usage. Neurobiology of Stress, 6, 78–93. http://doi.org/10.1016/j. ynstr.2016.08.002. Wissink, S., van Heerde, E. C., van der Burg, B., & van der Saag, P. T. (1998). A dual mechanism mediates repression of NF-κB activity by glucocorticoids. Molecular Endocrinology, 12(3), 355–363. http://dx.doi.org/10.1210/me.12.3.355. Y Palacios, R. D., Campo, A., Henningsen, K., Verhoye, M., Poot, D., Dijkstra, J., ... Van Der Linden, A. (2011). Magnetic resonance imaging and spectroscopy reveal differential hippocampal changes in anhedonic and resilient subtypes of the chronic mild stress rat model. Biological Psychiatry, 70(5), 449–457. http://dx.doi.org/10. 1016/j.biopsych.2011.05.014. Ye, Y., Wang, G., Wang, H., & Wang, X. (2011). Brain-derived neurotrophic factor (BDNF) infusion restored astrocytic plasticity in the hippocampus of a rat model of depression. Neuroscience Letters, 503(1), 15–19. http://dx.doi.org/10.1016/j.neulet. 2011.07.055.

functioning. Neuropsychology Review, 10(3), 57–66. http://doi.org/10.1023/ A:1009020914358. Hinwood, M., Morandini, J., Day, T., & Walker, F. (2012). Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. Cerebral Cortex, 22(6), 1442–1454. http://dx.doi.org/10.1093/ cercor/bhr229. Holsboer, F. (2000). The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology, 23(5), 477–501. http://doi.org/10.1016/S0893-133X(00) 00159-7. Jayatissa, M., Henningsen, K., Nikolajsen, G., West, M., & Wiborg, O. (2010). A reduced number of hippocampal granule cells does not associate with an anhedonia-like phenotype in a rat chronic mild stress model of depression. Stress, 13(2), 95–105. http://dx.doi.org/10.3109/10253890902951786. Jo, W. K., Zhang, Y., Emrich, H. M., & Dietrich, D. E. (2015). Glia in the cytokinemediated onset of depression: Fine tuning the immune response. Frontiers in Cellular Neuroscience, 9, 268. http://doi.org/http://dx.doi.org/%2010.3389/fncel.2015. 00268. Karagiannides, I., Golovatscka, V., Bakirtzi, K., Sideri, A., Salas, M., Stavrakis, D., ... Bradesi, S. (2014). Chronic unpredictable stress regulates visceral adipocytemediated glucose metabolism and inflammatory circuits in male rats. Physiological Reports, 2(5), e00284. http://dx.doi.org/10.14814/phy2.284. Kim, W., & Kim, S. K. (2016). Neural circuit remodeling and structural plasticity in the cortex during chronic pain. Korean Journal of Physiology and Pharmacology, 20(1), 1–8. http://doi.org/10.4196/kjpp.2016.20.1.1. Lautenbacher, S., Spernal, J., Schreiber, W., & Krieg, J. C. (1999). Relationship between clinical pain complaints and pain sensitivity in patients with depression and panic disorder. Psychosomatic Medicine, 61(6), 822–827. Levine, J. B., Kong, J., Nadler, M., & Xu, Z. (1999). Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS). Glia, 28(3), 215–224. http://dx.doi.org/10.1002/(SICI)1098-1136(199912) 28:3<215::AID-GLIA5>3.0.CO;2-C [pii]. Lin, E., Calvano, S. E., & Lowry, S. F. (2000). Inflammatory cytokines and cell response in surgery. Surgery, 127(2), 117–126. http://dx.doi.org/10.1067/msy.2000.101584. Lithwick, A., Lev, S., & Binshtok, A. M. (2013). Chronic pain-related remodeling of cerebral cortex – pain memory: A possible target for treatment of chronic pain. Pain Management, 3, 35–45. http://dx.doi.org/10.2217/pmt.12.74. Maes, M., Fišar, Z., Medina, M., Scapagnini, G., Nowak, G., & Berk, M. (2012). New drug targets in depression: Inflammatory, cell-mediate immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. and new drug candidates-Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology, 20(3), 127–150. http://doi.org/10.1007/s10787-011-0111-7. Maletic, V., Robinson, M., Oakes, T., Iyengar, S., Ball, S. G., & Russell, J. (2007). Neurobiology of depression: An integrated view of key findings. International Journal of Clinical Practice, 61(12), 2030–2040. http://doi.org/10.1111/j.1742-1241.2007. 01602.x. Martich, G. D., Boujoukos, A. J., & Suffredini, A. F. (1993). Response of man to endotoxin. Immunobiology, 187(3–5), 403–416. http://dx.doi.org/10.1016/S0171-2985(11) 80353-0. Merskey, H. (1965). The effect of chronic pain upon the response to noxius stimuli by psychiatric patients. Journal of Psychosomatic Research, 8, 405–419. http://dx.doi. org/10.1016/0022-3999(65)90083-8. Miguel-Hidalgo, J., Baucom, C., Dilley, G., Overholser, J., Meltzer, H., Stockmeier, C., & Rajkowska, G. (2000). Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder. Biological Psychiatry, 48(8), 861–873. Retrieved from http://www. scholaruniverse.com/ncbi-linkout?id=11063981. Miller, A. H., Maletic, V., & Raison, C. L. (2009). Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biological Psychiatry, 65(9), 732–740. http://doi.org/10.1016/j.biopsych.2008.11.029. Mizoguchi, K., Shoji, H., Ikeda, R., Tanaka, Y., & Tabira, T. (2008). Persistent depressive state after chronic stress in rats is accompanied by HPA axis dysregulation and reduced prefrontal dopaminergic neurotransmission. Pharmacology Biochemistry and Behavior, 91(1), 170–175. http://dx.doi.org/10.1016/j.pbb.2008.07.002. Moroz, B. T., Nuller, I. L., Ustimova, I. N., & Andreev, B. V. (1990). Study of pain sensitivity based on the indicators of electro- odontometry in patients with depersonalization and depressive disorders. Zhurnal Nevropatologii I Psikhiatrii Imeni S. S. Korsakova (Moscow, Russia: 1952), 90(10), 81–82. Munck, A., Guyre, P. M., & Holbrook, N. J. (1984). Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocrine Reviews, 5(1), 25–44. http://doi.org/10.1210/edrv-5-1-25. Ohayon, M. M., & Schatzberg, A. F. (2003). Using chronic pain to predict depressive morbidity in the general population. Archives of General Psychiatry, 60(1), 39–47. http://dx.doi.org/10.1001/archpsyc.60.1.39. Papp, M., Willner, P., & Muscat, R. (1991). An animal model of anhedonia: Attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress. Psychopharmacology, 104(2), 255–259. http://dx.doi.org/10.1007/ BF02244188. Paykel, E. S. (2006). Cognitive therapy in relapse prevention in depression. International Journal of Neuropsychopharmacology, 10(1), 131–136 Retrieved from http://www. ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16787553. Petrik, D., Lagace, D. C., & Eisch, A. J. (2012). The neurogenesis hypothesis of affective and anxiety disorders: Are we mistaking the scaffolding for the building? Neuropharmacology, 62(1), 21–34. http://dx.doi.org/10.1016/j.neuropharm.2011. 09.003. Pinto-Ribeiro, F., Almeida, A., Pêgo, J. M., Cerqueira, J., & Sousa, N. (2004). Chronic

173

Archives of Oral Biology 80 (2017) 164–174

F.M. Barbosa et al.

038. d’Audiffret, A. C., Frisbee, S. J., Stapleton, P. A., Goodwill, A. G., Isingrini, E., & Frisbee, J. C. (2010). Depressive behavior and vascular dysfunction: A link between clinical depression and vascular disease? Journal of Applied Physiology (Bethesda, Md.: 1985), 108(5), 1041–1051. http://dx.doi.org/10.1152/japplphysiol.01440.2009.

Young, E. A., Haskett, R. F., Murphy-Weinberg, V., Watson, S. J., & Akil, H. (1991). Loss of glucocorticoid fast feedback in depression. Archives of General Psychiatry, 48(8), 693–699. http://dx.doi.org/10.1001/archpsyc.1991.01810320017003. Zhang, M., Dai, W., Liang, J., Chen, X., Hu, Y., Chu, B., & Yu, S. (2013). Effects of UCMSinduced depression on nociceptive behaviors induced by electrical stimulation of the dura mater. Neuroscience Letters, 551, 1–6. http://doi.org/10.1016/j.neulet.2013.04.

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