Effects Of Repeated Stress Research Articles

Stress-mediated dysregulation of the Rap1 small GTPase impairs hippocampal structure and function

The effects of repeated stress on cognitive impairment are thought to be mediated, at least in part, by reductions in the stability of dendritic spines in brain regions critical for proper learning and memory, including the hippocampus. Small GTPases are particularly potent regulators of dendritic spine formation, stability, and morphology in hippocampal neurons. Through the use of small GTPase protein profiling in mice, we identify increased levels of synaptic Rap1 in the hippocampal CA3 region in response to escalating, intermittent stress. We then demonstrate that increased Rap1 in the CA3 is sufficient in and of itself to produce stress-relevant dendritic spine and cognitive phenotypes. Further, using super-resolution imaging, we investigate how the pattern of Rap1 trafficking to synapses likely underlies its effects on the stability of select dendritic spine subtypes. These findings illuminate the involvement of aberrant Rap1 regulation in the hippocampus in contributing to the psychobiological effects of stress.

Stress Elicits Contrasting Effects on Rac1-Cofilin Signaling in the Hippocampus and Amygdala.

There is accumulating evidence for contrasting patterns of stress-induced morphological and physiological plasticity in glutamatergic synapses of the hippocampus and amygdala. The same chronic stress that leads to the formation of dendritic spines in the basolateral amygdala (BLA) of rats, leads to a loss of spines in the hippocampus. However, the molecular underpinnings of these divergent effects of stress on dendritic spines are not well understood. Since the activity of the Rho GTPase Rac1 and the actin-depolymerizing factor cofilin are known to play a pivotal role in spine morphogenesis, we investigated if alterations in this signaling pathway reflect the differential effects of stress on spine plasticity in the hippocampus and amygdala. A day after the end of chronic immobilization stress (2 h/day for 10 days), we found a reduction in the activity of Rac1, as well as its effector p21-activated kinase 1 (PAK1), in the rat hippocampus. These changes, in turn, decreased cofilin phosphorylation alongside a reduction in the levels of profilin isoforms. In striking contrast, the same chronic stress increased Rac1, PAK1 activity, cofilin phosphorylation, and profilin levels in the BLA, which is consistent with enhanced actin polymerization leading to spinogenesis in the BLA. In the hippocampus, on the other hand, the same stress caused the opposite changes, the functional consequences of which would be actin depolymerization leading to the elimination of spines. Together, these findings reveal a role for brain-region specific differences in the dysregulation of Rac1-to-cofilin signaling in the effects of repeated stress on two brain areas that are implicated in the emotional and cognitive symptoms of stress-related psychiatric disorders.

Repeated Restraint Stress and Binge Alcohol during Adolescence Induce Long-Term Effects on Anxiety-like Behavior and the Expression of the Endocannabinoid System in Male Rats.

(1) Background: Negative experiences during adolescence increase the vulnerability to develop mental disorders later in life. A better understanding of the mechanisms underlying these long-term alterations could help to identify better therapeutic interventions. (2) Methods: Adolescent male Wistar rats were used to explore the effects of repeated stress and alcohol exposure on anxiety-like behaviors, plasma corticosterone levels and the gene expression of the endocannabinoid system (ECS) and other relevant signaling systems (glutamatergic, corticotropin-releasing hormone (CRH) and neuropeptide Y (NPY)) in the amygdala and the medial prefrontal cortex (mPFC). (3) Results: Overall, both stress and alcohol induced anxiety-like behaviors, but only the alcohol-exposed rats displayed increased plasma levels of corticosterone. In the amygdala, there was a general deficit in the gene expression of the ECS and increases in the mRNA levels of certain subunits of glutamate receptors. Interestingly, there were significant interaction effects between stress and alcohol on the expression of the NMDA receptor subunits. In addition, increased mRNA levels of the CRH receptor were observed in alcohol-exposed rats. In the mPFC, alcohol exposure was associated with an increase in the gene expression of the ECS. By contrast, the combination of stress and alcohol produced opposite effects. (4) Conclusions: In summary, early stress and alcohol exposure induced long-term anxiety-like behavior in male rats but different mechanisms are involved in these maladaptive changes in the brain.

Repeated stress leads to enhanced cortisol stress response in child social anxiety disorder but this effect can be prevented with CBT

Social anxiety disorder (SAD) is associated with continual social stress in everyday life. Two physiological components of stress are the hypothalamus–pituitary–adrenal axis, as captured by cortisol reactivity, and the autonomous nervous system, as captured by salivary alpha amylase (sAA) reactivity. In children with SAD, initial evidence points to dysregulated physiological stress reactivity for both systems. Furthermore, hardly any studies have assessed stress reactivity twice, including exploring possible changes after cognitive behavioral therapy (CBT). Children with SAD (n = 65; aged 9–13 years) and healthy controls (HCs, n = 55) participated in a social stress task (Trier Social Stress Test for Children, TSST-C), which was repeated with children with SAD after either 12 sessions of CBT or a waiting period to explore possible habituation or sensitization effects. Before treatment, children in the SAD and HC groups did not differ in their cortisol stress reactivity toward the TSST-C but did differ in their sAA response with a more pronounced response in the SAD group. After treatment, children with SAD in the waitlist group differed from children with SAD in the CBT group by showing stronger cortisol reactivity and a higher responder rate, indicative of a possible sensitization to stress. No difference was found for sAA. Future research should compare children with SAD and HC children concerning the effect of repeated stress on sensitization.

Sex-specific differences in corticosterone secretion, behavioral phenotypes and expression of TrkB.T1 and TrkB.FL receptor isoforms: Impact of systemic TrkB inhibition and combinatory stress exposure in adolescence

Stress exposure has been implicated in the development of mood disorders, although little is known about the lasting effects of repeated stress during the adolescent period on sex-specific differences in endocrine and plasticity-signaling responses in adulthood. Using a 10-day combinatory stress paradigm (postnatal day (PND) 26 to 35), we examined sex-specific impact of adolescent stress and inhibition of tyrosine-related kinase B (TrkB) receptor (ANA-12; 0.5 mg/kg, i.p.) on 1) adolescent blood corticosterone levels, 2) adult locomotion and anxiety-like behavior, and 3) region-specific differences in endogenous TrkB full-length (TrkB.FL) and truncated (TrkB.T1) receptor isoforms. Blood collected on days 1, 5 and 10 revealed elevated basal and stress-induced CORT secretion in females compared to males, while ANA-12 attenuated CORT elevations post stress in both sexes. As adults, all females exhibited higher locomotor and exploratory activity than males in the open field test and elevated plus maze, and differences were comparable in the forced swim within stress-naïve and stress groups. Biochemically, vehicle-treated males showed elevated TrkB.T1 and TrkB.FL compared to vehicle-treated females in the PFC, hippocampus and NAc, and levels were consistently attenuated by ANA-12 treatment in non-stress males. With regards to stress exposure, expression of both isoforms was strongly down-regulated in the NAc of males only and was associated with increased TrkB.T1 in the PFC. ANA-12 enhanced expression in females, independent of stress exposure, compared to vehicle-treated counterparts, expression being increased for TrkB.T1 versus TrkB.FL and magnitude of the changes being region-specific. In contrast, ANA-12 effects in stressed males were restricted to inhibition of both isoforms in the hippocampus. Together, our findings support that TrkB activation, contingent on stress exposure, differentially affects TrkB isoform regulation during adulthood. Sex-specific biochemical responses at delayed intervals following adolescent stress exposure further support the need to include the sex variable in animal models.

Neuroplasticity in the maternal hippocampus: Relation to cognition and effects of repeated stress

This article is part of a Special Issue “Parental Care”. It is becoming clear that the female brain has an inherent plasticity that is expressed during reproduction. The changes that occur benefit the offspring, which in turn secures the survival of the mother's genetic legacy. Thus, the onset of maternal motivation involves basic mechanisms from genetic expression profiles, to hormone release, to hormone–neuron interactions, all of which fundamentally change the neural architecture — and for a period of time that extends, interestingly, beyond the reproductive life of the female. Although multiple brain areas involved in maternal responses are discussed, this review focuses primarily on plasticity in the maternal hippocampus during pregnancy, the postpartum period and well into aging as it pertains to changes in cognition. In addition, the effects of prolonged and repeated stress on these dynamic responses are considered. The maternal brain is a marvel of directed change, extending into behaviors both obvious (infant-directed) and less obvious (predation, cognition). In sum, the far-reaching effects of reproduction on the female nervous system provide an opportunity to investigate neuroplasticity and behavioral flexibility in a natural mammalian model.

Distinct Effects of Repeated Restraint Stress on Basolateral Amygdala Neuronal Membrane Properties in Resilient Adolescent and Adult Rats

Severe and repeated stress has damaging effects on health, including initiation of depression and anxiety. Stress that occurs during development has long-lasting and particularly damaging effects on emotion. The basolateral amygdala (BLA) plays a key role in many affective behaviors, and repeated stress causes different forms of BLA hyperactivity in adolescent and adult rats. However, the mechanism is not known. Furthermore, not every individual is susceptible to the negative consequences of stress. Differences in the effects of stress on the BLA might contribute to determine whether an individual will be vulnerable or resilient to the effects of stress on emotion. The purpose of this study is to test the cellular underpinnings for age dependency of BLA hyperactivity after stress, and whether protective changes occur in resilient individuals. To test this, the effects of repeated stress on membrane excitability and other membrane properties of BLA principal neurons were compared between adult and adolescent rats, and between vulnerable and resilient rats, using in vitro whole-cell recordings. Vulnerability was defined by adrenal gland weight, and verified by body weight gain after repeated restraint stress, and fecal pellet production during repeated restraint sessions. We found that repeated stress increased the excitability of BLA neurons, but in a manner that depended on age and BLA subnucleus. Furthermore, stress resilience was associated with an opposite pattern of change, with increased slow afterhyperpolarization (AHP) potential, whereas vulnerability was associated with decreased medium AHP. The opposite outcomes in these two populations were further distinguished by differences of anxiety-like behavior in the elevated plus maze that were correlated with BLA neuronal excitability and AHP. These results demonstrate a substrate for BLA hyperactivity after repeated stress, with distinct membrane properties to target, as well as age-dependent factors that contribute to resilience to the effects of stress.

Repeated restraint stress exerts different impact on structure of neurons in the lateral and basal nuclei of the amygdala

Chronic stress exacerbates and can induce symptoms of depression and anxiety disorders. Chronic stress causes amygdala hyperactivity, which may contribute to these detrimental effects. One potential mechanism for amygdala hyperactivity is an increase of excitatory drive after stress. Excitatory inputs to the amygdala predominantly synapse upon dendritic spines, and repeated stress has been demonstrated to increase dendritic spines in the basolateral amygdala (BLA). However, the BLA is comprised of several nuclei, including the lateral nucleus (LAT) and the basal nucleus (BA), which exert functionally distinct roles in amygdala-dependent behaviors. Furthermore, while an increase of dendritic spines can impart significant functional ramifications, a shift of spine distribution can also exert significant impact. However, differences in the effects of repeated stress on LAT and BA have not been examined, nor differential effects on spine distribution. This study examined the effects of repeated restraint stress on dendritic structure of principal neurons from the LAT and BA in Golgi-stained tissue. This study found that repeated stress increased spine number in LAT and BA, but in very distinct patterns, with proximal increases in LAT neurons and non-proximal increases in BA neurons. Furthermore, repeated stress increased dendritic length in the BA, but not the LAT, leading to a global change of spine density in BA, but a focal change in LAT. These distinct effects of repeated stress in the LAT and BA may exert significant functional effects on fear behavior, and may underlie differences in the effects of repeated stress on acquisition, contextual modulation and extinction of fear behavior.

Migraine: Maladaptive Brain Responses to Stress

Migraine offers a unique model to understand the consequences of repeated stressors on the brain. Repeated stressors can alter the normal response of physiological systems, and this concept has been termed "allostatic load." In the case of the brain, the effects of repeated stress may lead to alteration in brain networks both functionally and structurally. As a result, the brain responds abnormally to environmental conditions (psychological or physiological). Here, we present an alternative perspective on migraine disease and propose that changes in brain states may occur as a result of repeated migraine attacks through maladaptive coping mechanisms. The cascade of these effects can lead to further deterioration of adaptation and thus lead to transformation or chronification of the disease.

Acute and repeated stress differentially regulates behavioral, endocrine, neural parameters relevant to emotional and stress response in young and aged rats

Aging is associated with dysregulation of emotional and endocrine responses in a stressful environment. To understand the developmental mechanisms of stress vulnerability with aging, we investigated the effects of repeated stress on behavioral, endocrine, and neural parameters relating to emotional and stress responses in young (3 months old) and aged (24 months old) F344/N male rats. Young and aged rats were either subjected to 1-h restraint stress for 14 consecutive days or left undisturbed. After the procedures, behaviors were examined in open-field and elevated plus-maze tests to evaluate the level of anxiety induced by aging and repeated stress. Following the behavioral tests, serum corticosterone concentrations and c-Fos immunoreactivity throughout the brain in response to acute restraint stress were examined. Control and repeatedly stressed aged rats showed more anxiety-related behaviors than control and repeatedly stressed young rats in both tests. In particular, repeatedly stressed aged rats showed more anxiety-related behaviors in the elevated plus-maze than control aged and repeatedly stressed young rats, although stressed young rats were not different from control young rats. Repeatedly stressed aged rats showed higher serum corticosterone concentrations in response to acute stress than subjects in all other conditions. In c-Fos expression, control aged rats showed decreases in c-Fos-positive cells in response to acute stress in the prefrontal cortex, medial preoptic area, bed nucleus of the stria terminalis, nucleus accumbens, medial amygdaloid nucleus, and CA3 subfield of hippocampus, whereas they showed increases in the dorsal raphe nucleus and parvocellular part of the paraventricular nucleus of the hypothalamus compared to acutely stressed control young rats. These results indicate that repeated stress enhances emotional and stress responses in aged rats but not in young rats, suggesting that aging causes organisms to become vulnerable to stress, which might be mediated by dysfunction of the brain system regulating emotional and stress responses.

Gulf War illness: Effects of repeated stress and pyridostigmine treatment on blood–brain barrier permeability and cholinesterase activity in rat brain

After the first Persian Gulf War, many soldiers have complained of a variety of symptoms designated as “Gulf War Illness”. Among several factors, implication of pyridostigmine (PB) in late cognitive dysfunction is highly likely. As a hypothesis to explain these behavioural disorders is a potentiation of the operational stress effects by pyridostigmine. We have previously described that repeated stress combined to pyridostigmine treatment induces learning dysfunction linked to genomic cerebral modifications [Barbier L, Diserbo M, Lamproglou I, Amourette C, Peinnequin A, Fauquette W. Repeated stress in combination with pyridostigmine: part II—changes in selected cerebral genes expression. Behav Brain Res 2009;197:292–300; Lamproglou I, Barbier L, Diserbo M, Fauvelle F, Fauquette W, Amourette C. Repeated stress in combination with pyridostigmine: part I—long-term behavioural consequences. Behav Brain Res 2009;197:301–10]. In the present study, using the same experimental model, we attempted to determine if such modifications are linked to a central passage of pyridostigmine under stress. Indeed it is known that exposure to stress can disrupt blood–brain barrier (BBB) and thereby increase the neurotoxicity induced by chemicals in many cerebral areas. Adult rats were subjected to repeated stress based on a modification of the pole climbing avoidance technique and treated daily by PB (1.5 mg/kg/day, oral in water), for two 5-day periods separated by 2-day rest. Just after the last stress session, 3H-pyridostigmine was administered as a tracer to evaluate BBB breakdown. In brain micro-punches and brain coronal cryosections, we failed to detect any radioactivity in animals chronically stressed and treated by pyridostigmine. Accordingly, no change of ChE activity was noted in any brain area studied. It thus appears that, in our experimental model, pyridostigmine induces effects on central nervous system, but these effects do not seem to be mediated by a central passage of pyridostigmine linked to a BBB opening under stress. These results suggest that pyridostigmine may have central effects, under stress, via indirect mechanisms emerging from a peripheral pathway.

P03-258 Enhanced and delayed stress-induced body weight in mice lacking functional natriuretic peptide-a receptors

Genetic and environmental influences are both known to be causal factors in the development and maintenance of obesity. Stress related chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and resulting increased glucocorticoid exposure is known to be an important pathophysiological mechanism in the development of obesity. We show that the natriuretic peptide system, that mediates endocrine and behavioural responses to stress, plays a role in the control of long-term body weight in chronically ethanol drinking mice. In mice lacking functional NPR-A receptors, physical, and in particular psychological stress leads to enhanced and continuous increase in body weight in homozygote NPR-A mice. The effect of repeated stress on body weight appeared rapidly and persisted throughout life. Over a longer period of time without stress, body weights do not differ between the different genotypes. Moreover, we could demonstrate that NPR-A homozygote mice show significant higher corticosterone levels following stress. Heterozygote animals show an intermediate phenotype concerning body weights and corticosterone levels following stress. Alterations in the NPR-A receptor gene may constitute a genetic risk factor for stress-induced eating and obesity.

Acute and repeated restraint stress influences cellular damage in rat hippocampal slices exposed to oxygen and glucose deprivation

Several studies have shown that high corticosteroid hormone levels increase neuronal vulnerability. Here we evaluate the consequences of in vivo acute or repeated restraint stress on cellular viability in rat hippocampal slices suffering an in vitro model of ischemia. Cellular injury was quantified by measuring lactate dehydrogenase (LDH) and neuron-specific enolase released into the medium. Acute stress did not affect cellular death when oxygen and glucose deprivation (OGD) was applied both immediately or 24 h after restraint. The exposure to OGD, followed by reoxygenation, resulted in increased LDH in the medium. Repeated stress potentiated the effect of OGD both, on LDH and neuron-specific enolase released to the medium. There was no effect of repeated stress on the release of S100B, an astrocytic protein. Additionally, no effect of repeated stress was observed on glutamate uptake by the tissue. These results suggest that repeated stress increases the vulnerability of hippocampal cells to an in vitro model of ischemia, potentiating cellular damage, and that the cells damaged by the exposure to repeated stress + OGD are mostly neurons. The uptake of glutamate was not observed to participate in the mechanisms responsible for rendering the neurons more susceptible to ischemic damage after repeated stress.

Molecular mechanisms of neuroplasticity and pharmacological implications: the example of tianeptine

The hippocampal formation, which expresses high levels of adrenal steroid receptors, is a malleable brain structure that is important for certain types of learning and memory. This structure is also vulnerable to the effects of stress hormones which have been reported to be increased in depressed patients, particularly those with severe depression. The amygdala, a structure that plays a critical role in fear learning, is also an important target of anxiety and stress. Certain animal models of depression involve application of repeated stress. Repeated stress promotes behavioral changes that can be associated with these two brain structures such as impairment of hippocampus-dependent memory and enhancement of fear and aggression, which are likely to reflect amygdala function. At a cellular level, opposite responses in the hippocampus and amygdala are observed, namely, shrinkage of dendrites in hippocampus and growth of dendrites in the lateral amygdala, involving in both cases a remodeling of dendrites. Furthermore, stress-induced suppression of neurogenesis has been noted in dentate gyrus. At a molecular level, the effects of repeated stress in the hippocampus involve excitatory amino acids and the induction of the glial form of the glutamate transporter. Chronic treatment with the antidepressant tianeptine may prevent these effects in hippocampus and amygdala.

In vitro deformation of acetyl resin and metal alloy removable partial denture direct retainers

Statement of the problem Acetyl resin removable partial denture (RPD) direct retainers may provide an esthetic alternative to conventional metal direct retainers. The effect of repeated stress on acetyl resin direct retainers is unknown. Purpose This study compared deformation of acetyl resin and metal alloy RPD direct retainers after repeated dislodgments over a test die. Material and methods Ten acetyl resin (Thermoflex) and 10 metal alloy (Ticonium Premium 100) RPD direct retainers, fabricated to manufacturers' specifications, were dislodged over a stainless steel die by means of a laboratory test apparatus for a simulated 3-year period (5000 cycles). Occlusal and facial digital images made before and after cycling were measured (mm) for direct retainer deformation by using computer-imaging software (Scion Image 1.62). Student t tests (α=.05) were performed for statistical comparisons. Results A significant difference in deformation between acetyl resin and metal alloy direct retainers occurred in the occlusal view ( P=.045), but not in the facial view ( P=.832). Average deformation varied but was greatest in the occlusal view: 0.09 ± 0.8 mm for acetyl resin direct retainers compared with 0.01 ± 0.9 mm for metal alloy direct retainers. Average facial view deformations revealed no significant differences: 0.039 ± 0.6 mm for metal alloy and 0.033 ± 0.7 mm for acetyl resin direct retainers. Conclusion Within the limitations of this in vitro study, significantly greater deformation resulted with acetyl resin compared with metal alloy direct retainers after 3 years of simulated use.

Effects of repeated stress on regeneration of serotonergic and noradrenergic axons in the cerebral cortex of adult rats

We examined whether regeneration of serotonergic (5-HT) and noradrenergic (NA) axons might be affected by stress. Neurotoxins to 5-HT or NA axons were injected into the frontal cortex to cause partial denervation. Mild restraint stress (40 min/day) was started 16 days later and given for 14 consecutive days (30-day stressed group). Non-stressed animals were divided into two groups, animals sacrificed at 14 days (14-day control group) and those sacrificed at 30 days (30-day control group) after the toxin injection. In immunohistochemical study, the denervation area of 5-HT axons but not that of NA axons was significantly smaller in the 30-day control group than in the 14-day control group. However, there was no significant difference between the 14-day control and 30-day stressed groups. These findings suggested that regeneration of 5-HT axons occurred earlier than that of NA axons, and that stress exerted inhibitory influence on regeneration of 5-HT axons.

Enhanced and delayed stress-induced alcohol drinking in mice lacking functional CRH1 receptors.

There is a relation between stress and alcohol drinking. We show that the corticotropin-releasing hormone (CRH) system that mediates endocrine and behavioral responses to stress plays a role in the control of long-term alcohol drinking. In mice lacking a functional CRH1 receptor, stress leads to enhanced and progressively increasing alcohol intake. The effect of repeated stress on alcohol drinking behavior appeared with a delay and persisted throughout life. It was associated with an up-regulation of the N-methyl-d-aspartate receptor subunit NR2B. Alterations in the CRH1 receptor gene and adaptional changes in NR2B subunits may constitute a genetic risk factor for stress-induced alcohol drinking and alcoholism.

Moderate Psychosocial Stress Appears Not to Impair Recall of Words Learned 4 Weeks Prior to Stress Exposure

Recent studies in humans have reported that recall of previously learned material is especially sensitive to the disruptive effects of pharmacologically induced cortisol elevations. Whether similar effects occur after exposure to psychosocial stress remains to be shown. Moreover it is unknown whether stress before or after the initial learning interacts with the later effects of repeated stress on delayed recall (e.g. state-dependent learning). Forty subjects participated in the present experiment. They learned a word list either one hour before or 10 u min after exposure to a psychosocial laboratory stressor. Delayed recall was tested 4 weeks later, again either before or after stress. Salivary cortisol levels increased significantly in response to both stress exposures. Stress had no effects on the initial learning and also did not impair delayed recall. Moreover there was no evidence for state-dependent learning. The current data seem to be in conflict with previous studies demonstrating that delayed recall is especially sensitive to elevated cortisol levels. Several reasons for these discrepancies are discussed. Among them is the small sample size, the moderate cortisol increase in response to the second stress exposure but also the long recall delay, which might lead to memory traces less susceptible to stress.

Caesarean Section Birth Produces Long Term Changes in Dopamine D1 Receptors and in Stress-induced Regulation of D3 and D4 Receptors in the Rat Brain

Schizophrenia is associated with increased birth complications and altered mesocorticolimbic dopaminergic (DA) transmission, whereas stress also influences psychotic symptoms. Given this, the present study tested effects of two birth complications, Caesarean section (C-section) birth with or without acute global anoxia, on brain DA receptors in rats at adulthood. Effects of repeated stress at adulthood were also tested. Before stress, C-sectioned rats showed increased D1-like receptor binding in limbic areas, compared to vaginally born controls. There were no differences between birth groups in D2-like, D3, or D4-like receptor binding before stress. After stress, C-sectioned animals showed decreased D3 receptors in accumbens and increased D4-like receptors in dorsal striatum, accumbens, and olfactory tubercles, compared to vaginal birth. This occurred because stress upregulated D3 receptors only with vaginal birth and upregulated D4-like receptors only with C-section. Animals born by C-section + anoxia showed no change in DA receptors relative to vaginal birth, before or after stress. It is concluded that interactions between an individual's experience of stress at adulthood, together with other environmental events in their history, such as birth complications, can be important determinants of brain DA receptor levels.

Effect of repeated stress on novelty-induced antinociception in rats.

There is extensive evidence that acute stress induces an analgesic response in rats. On the other hand, repeatedly stressed animals may present the opposite effect, i.e., hyperalgesia. Furthermore, exposure to novelty is known to induce antinociception. The effects of repeated restraint stress on nociception after exposure to novelty, as measured by the tail-flick latency (TFL), were studied in adult male rats. The animals were stressed by restraint 1 h daily, 5 days a week for 40 days. The control group was not submitted to restraint. Nociception was assessed with a tail-flick apparatus. After being familiarized with the TFL apparatus, each group was subdivided into two other groups, i.e., with or without novelty. Animals were subjected to the TFL measurement twice. For the animals exposed to novelty, the first TFL measurement was made immediately before, and the second 2 min after a 2-min exposure to a new environment. While the control group presented an increased TFL after exposure to a novel environment, chronically stressed animals did not show this effect. These results suggest that repeated restraint stress induces an alteration in the nociceptive response, perhaps as a result of an alteration in endogenous opioids in these animals.