ABSTRACT
Although pain and cognitive deficits are widespread and debilitating symptoms of multiple sclerosis (MS), they remain poorly understood. Theiler's murine encephalomyelitis virus (TMEV) infection is an animal model of MS where disease course is exacerbated by prior stressors. Here chronic infection coupled with prior social stress increased pain behavior and impaired hippocampal-dependent memory consolidation during the demyelinating phase of disease in SJL mice. These results suggest that the TMEV model may be useful in investigating pain and cognitive impairments in MS. However, in contrast to prior Balb/cJ studies, stress failed to consistently alter behavioral and physiological indicators of disease course.
Subject(s)
Cardiovirus Infections/psychology , Cognition/physiology , Pain/etiology , Stress, Psychological/complications , Animals , Behavior, Animal , Cardiovirus Infections/complications , Disease Models, Animal , Male , Mice , Multiple Sclerosis/complications , Multiple Sclerosis/psychology , TheilovirusABSTRACT
Previous research has shown that neonatal handling has prolonged protective effects associated with stress resilience and aging, yet little is known about its effect on stress-induced modulation of infectious disease. We have previously demonstrated that social disruption stress exacerbates the acute and chronic phases of the disease when applied prior to Theiler's virus infection (PRE-SDR) whereas it attenuates disease severity when applied concurrently with infection (CON-SDR). Here, we asked whether neonatal handling would protect adult mice from the detrimental effects of PRE-SDR and attenuate the protective effects of CON-SDR on Theiler's virus infection. As expected, handling alone decreased IL-6 and corticosterone levels, protected the non-stressed adult mice from motor impairment throughout infection and reduced antibodies to myelin components (PLP, MBP) during the autoimmune phase of disease. In contrast, neonatal handling X PRE/CON-SDR elevated IL-6 and reduced corticosterone as well as increased motor impairment during the acute phase of the infection. Neonatal handling X PRE/CON-SDR continued to exacerbate motor impairment during the chronic phase, whereas only neonatal handling X PRE-SDR increased in antibodies to PLP, MOG, MBP and TMEV. Together, these results imply that while handling reduced the severity of later Theiler's virus infection in non-stressed mice, brief handling may not be protective when paired with later social stress.
Subject(s)
Cardiovirus Infections/immunology , Handling, Psychological , Social Behavior , Stress, Psychological/immunology , Theilovirus/immunology , Acute Disease , Age Factors , Animals , Animals, Newborn , Chronic Disease , Interleukin-6/immunology , Male , Mice , Mice, Inbred BALB C , Motor Activity/immunology , Myelin Proteins/immunologyABSTRACT
Chronic social disruption stress (SDR) exacerbates acute and chronic phase Theiler's murine encephalomyelitis virus (TMEV) infection, a mouse model of multiple sclerosis. However, the precise mechanism by which this occurs remains unknown. The present study suggests that SDR exacerbates TMEV disease course by priming virus-induced neuroinflammation. It was demonstrated that IL-1ß mRNA expression increases following acute SDR; however, IL-6 mRNA expression, but not IL-1ß, is upregulated in response to chronic SDR. Furthermore, this study demonstrated SDR prior to infection increases infection related central IL-6 and IL-1ß mRNA expression, and administration of IL-6 neutralizing antibody during SDR reverses this increase in neuroinflammation.
Subject(s)
Encephalitis, Viral/immunology , Encephalitis, Viral/pathology , Gene Expression Regulation, Viral/immunology , Interleukin-6/metabolism , Social Environment , Stress, Psychological/immunology , Stress, Psychological/pathology , Theilovirus/immunology , Animals , Chronic Disease , Disease Models, Animal , Encephalitis, Viral/genetics , Interleukin-1beta/biosynthesis , Interleukin-1beta/genetics , Interleukin-6/biosynthesis , Interleukin-6/genetics , Male , Mice , Mice, Inbred BALB C , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Multiple Sclerosis/virology , Random Allocation , Stress, Psychological/genetics , Up-Regulation/genetics , Up-Regulation/immunologyABSTRACT
Previous studies have established a link between adverse early life events and subsequent disease vulnerability. The present study assessed the long-term effects of neonatal maternal separation on the response to Theiler's murine encephalomyelitis virus infection, a model of multiple sclerosis. Balb/cJ mouse pups were separated from their dam for 180-min/day (180-min MS), 15-min/day (15-min MS), or left undisturbed from postnatal days 2-14. During adolescence, mice were infected with Theiler's virus and sacrificed at days 14, 21, or 35 post-infection. Prolonged 180-min MS increased viral load and delayed viral clearance in the spinal cords of males and females, whereas brief 15-min MS increased the rate of viral clearance in females. The 15-min and 180-min MS mice exhibited blunted corticosterone responses during infection, suggesting that reduced HPA sensitivity may have altered the immune response to infection. These findings demonstrate that early life events alter vulnerability to CNS infection later in life. Therefore, this model could be used to study gene-environment interactions that contribute to individual differences in susceptibility to infectious and autoimmune diseases of the CNS.
Subject(s)
Immune System/physiology , Theilovirus/metabolism , Animals , Corticosterone/metabolism , Encephalitis/immunology , Encephalitis/virology , Environment , Female , Male , Mice , Mice, Inbred BALB C , Models, Genetic , Spinal Cord/pathology , Time Factors , Tissue Distribution , Viral LoadABSTRACT
Stressful life events have been associated with the onset and/or exacerbation of multiple sclerosis (MS). Our previous studies have indicated that restraint stress (RS) reduces inflammation and virus-induced chemokine expression in the Theiler's virus-induced demyelination (TVID) model of MS. Here we report that RS significantly reduced the virus-induced interferon-gamma mRNA levels in the brain. Additionally, mRNA levels of lymphotoxin-beta, tumor necrosis factor-alpha, and interferon-gamma in the brain were negatively correlated with viral titers in the brain. These results indicated an immunosuppressive effect of stress during early TVID causing impaired viral clearance, which may be a potential exacerbating factor for later demyelination.
Subject(s)
Brain/immunology , Cardiovirus Infections/immunology , Cytokines/biosynthesis , Stress, Psychological/immunology , Animals , Blotting, Western , Brain/pathology , Brain/virology , Disease Models, Animal , Inflammation/immunology , Male , Mice , Mice, Inbred CBA , Multiple Sclerosis/immunology , RNA, Messenger/analysis , Restraint, Physical , Reverse Transcriptase Polymerase Chain Reaction , Theilovirus/immunologyABSTRACT
Restraint stress (RS) applied to mice during acute infection with Theiler's virus causes corticosterone-induced immunosuppression. This effect was further investigated by measuring chemokine changes in the spleen and central nervous system (CNS) using an RNase Protection Assay. mRNAs for lymphotactin (Ltn), interferon-induced protein-10 (IP-10), MIP-1 beta, monocyte chemoattractant protein-1 (MCP-1) and TCA-3 were detected in the spleen at day 2 pi, but not in the brain of CBA mice infected with Theiler's virus. Ltn, IP-10 and RANTES were elevated in both the spleen and the brain at day 7 pi, and were significantly decreased by RS in the brain. RS also resulted in decreased inflammation within the CNS.
Subject(s)
Brain/immunology , Cardiovirus Infections/immunology , Chemokines/biosynthesis , Stress, Psychological/immunology , Theilovirus/metabolism , Animals , Brain/pathology , Brain/virology , Cardiovirus Infections/physiopathology , Male , Mice , RNA, Messenger/analysis , Restraint, Physical , Spleen/immunology , Spleen/pathology , Spleen/virology , Thymus Gland/immunology , Thymus Gland/pathology , Thymus Gland/virologyABSTRACT
Our laboratory has previously shown that restraint stress resulted in decreased Theiler's virus-induced CNS inflammation, while exacerbating illness behaviors during the acute phase of disease. In contrast, social disruption stress (SDR) applied prior to infection led to the development of glucocorticoid (GC) resistance, and these animals developed more severe disease course, with increased inflammation. However, when SDR was applied concurrent with infection, GC resistance fails to develop, disease course is less severe and inflammation was moderate. These results suggest that the effects of SDR on Theiler's virus infection are dependent upon the timing of SDR application in relation to infection.
Subject(s)
Cardiovirus Infections/physiopathology , Stress, Physiological/complications , Theilovirus , Acute Disease , Analysis of Variance , Animals , Behavior, Animal , Cardiovirus Infections/virology , Corticosterone/blood , Gliosis/etiology , Male , Meningitis/etiology , Meningitis/pathology , Mice , Mice, Inbred BALB C , Random Allocation , Spinal Cord/pathology , Time FactorsABSTRACT
Psychological stress is thought to play an important role in multiple sclerosis. We have been investigating the role of restraint stress in Theiler's virus infection in mice as a model for multiple sclerosis. We have previously determined that restraint stressed CBA mice had higher levels of mortality following infection with Theiler's virus. We proposed that this was due to high levels of stress-induced corticosterone, which resulted in decreased numbers of circulating lymphocytes, decreased inflammatory cell infiltrates into the brain and consequently decreased viral clearance from the central nervous system (CNS). The effect of restraint stress on the innate immune response to Theiler's virus is further investigated in the current study. Restraint stressed mice developed clinical signs of encephalitis, thymic atrophy, and adrenal hypertrophy. Decreased numbers of circulating lymphocytes and increased numbers of neutrophils were observed in the stressed mice. Stressed mice also had lower numbers of spleen cells which correlated with the decreased numbers of lymphocytes in circulation. Restraint stress caused elevations in serum tumor necrosis alpha (TNF-alpha). Virus-induced natural killer cell (NK) cytotoxic activity was significantly reduced in restrained mice at one day post infection which may account for the reduced viral clearance from the CNS. These data suggest that stress-induced immunosuppression of cytolytic NK cell activity may account in part for the reduced ability to clear virus from the CNS and increased mortality observed in this model.
Subject(s)
Cardiovirus Infections/immunology , Interleukin-1/blood , Killer Cells, Natural/immunology , Stress, Psychological/immunology , Theilovirus/immunology , Tumor Necrosis Factor-alpha/analysis , Acute Disease , Animals , Encephalitis, Viral/immunology , Encephalitis, Viral/virology , Leukocyte Count , Male , Mice , Mice, Inbred CBA , Restraint, Physical , Serum/chemistry , Spleen/immunology , Spleen/virology , Stress, Psychological/virology , Theilovirus/pathogenicityABSTRACT
Restraint stress was found to have a profound effect on the acute phase of Theiler's virus infection. Increased mortality rates were observed in restrained CBA mice infected with the BeAn strain of Theiler's virus. In addition, restrained mice developed higher CNS viral titers than infected/nonrestrained mice. Thymic atrophy was observed in both infected and uninfected restrained mice. Decreased microgliosis, perivascular cuffing, and astrocytosis were observed in restrained mice compared to nonrestrained infected mice at 7 days postinfection. Restraint-stressed mice also developed decreased numbers of lymphocytes and increased numbers of neutrophils in the blood. The mechanism proposed for these alterations involves stress-induced corticosterone, which causes immunosuppression, decreased trafficking of inflammatory cells in the CNS, and, consequently, increased viral replication.
Subject(s)
Cardiovirus Infections/complications , Cardiovirus Infections/etiology , Central Nervous System Diseases/virology , Restraint, Physical , Theilovirus , Acute Disease , Animals , Cardiovirus Infections/mortality , Cardiovirus Infections/physiopathology , Central Nervous System/pathology , Central Nervous System Diseases/mortality , Central Nervous System Diseases/pathology , Central Nervous System Diseases/physiopathology , Corticosterone/blood , Leukocyte Count , Male , Mice , Mice, Inbred CBA , Thymus Gland/pathologyABSTRACT
Brief-moderate shock (3, 0.75 s, 1.0 mA) has opposite effects on different measures of pain, inducing antinociception on the tail-flick test while lowering vocalization thresholds to shock and heat (hyperalgesia) and enhancing fear conditioned by a gridshock unconditioned stimulus (US). This study examined the generality of shock-induced hyperalgesia under a range of conditions and explored parallels to sensitized startle. Reduced vocalization thresholds to shock and antinociception emerged at a similar shock intensity. Severe shocks (3, 25 s, 1.0 mA or 3, 2 s, 3.0 mA) lowered vocalization threshold to shock but increased vocalization and motor thresholds to heat and undermined fear conditioned by a gridshock or a startling tone US. All shock schedules facilitated startle, but only brief-moderate shock inflated fear conditioning. The findings suggest that brief-moderate shock enhances the affective impact of aversive stimuli, whereas severe shocks attenuate pain.
Subject(s)
Hyperalgesia/etiology , Shock/complications , Affect , Animals , Behavior, Animal/physiology , Conditioning, Psychological , Fear , Hyperalgesia/diagnosis , Learning , Male , Nociceptors/physiology , Rats , Rats, Sprague-Dawley , Reflex, Startle/physiology , Vocalization, Animal/physiologyABSTRACT
This study evaluated the psychometric characteristics of the Beck Depression Inventory-II (BDI-II; A. T. Beck, R. A. Steer, & G. K. Brown, 1996) in a primary care medical setting. A principal-components analysis with Promax rotation indicated the presence of 2 correlated factors, Somatic-Affective and Cognitive, which explained 53.5% of the variance. A hierarchical, second-order analysis indicated that all items tap into a second-order construct of depression. Evidence for convergent validity was provided by predicted relationships with subscales from the Short-Form General Health Survey (SF-20; A. L. Stewart, R. D. Hayes, & J. E. Ware, 1988). A receiver operating characteristic analysis demonstrated criterion-related validity: BDI-II scores predicted a diagnosis of major depressive disorder (MDD), as determined by the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ). This study demonstrated that the BDI-II yields reliable, internally consistent, and valid scores in a primary care medical setting, suggesting that use of the BDI-II in this setting may improve detection and treatment of depression in these medical patients.
Subject(s)
Depressive Disorder/diagnosis , Primary Health Care , Psychiatric Status Rating Scales/standards , Adolescent , Adult , Female , Humans , Male , Mass Screening , Middle Aged , Psychiatric Status Rating Scales/statistics & numerical data , Psychometrics , Sensitivity and SpecificityABSTRACT
OBJECTIVE AND METHODS: Two experiments examined the impact of viewing unpleasant, pleasant, and neutral photographic slides on cold-pain perception in healthy men and women. In each experiment, participants viewed one of three slide shows (experiment 1 = fear, disgust, or neutral; experiment 2 = erotic, nurturant, or neutral) immediately before a cold-pressor task. Skin conductance and heart rate were recorded during the slide shows, whereas visual analog scale ratings of pain intensity and unpleasantness thresholds and pain tolerance were recorded during the cold-pressor task. RESULTS: Viewing fear and disgust slides decreased pain intensity and unpleasantness thresholds, but only the fear slides decreased pain tolerance. In contrast, viewing erotic, but not nurturant, slides increased pain intensity and unpleasantness threshold ratings on the visual analog scale in men, whereas neither nurturant nor erotic slides altered pain tolerance. CONCLUSIONS: These results are consistent with a motivational priming model that predicts that unpleasant affective states should enhance pain and that pleasant affective states should attenuate it.
Subject(s)
Cold Temperature , Emotions/physiology , Pain Threshold/psychology , Adult , Affect/physiology , Arousal/physiology , Female , Humans , Male , Models, Psychological , Motivation , Pain Measurement , Sex FactorsABSTRACT
RATIONALE: The anxiogenic DMCM, an inverse benzodiazepine agonist, was used to explore the relationship between negative affective states and pain. Past work suggests that the outcome obtained may depend on both the intensity of the affective state and the way in which pain is inferred. OBJECTIVES: The present study was designed to test the impact of relatively low doses of DMCM on multiple measures of pain reactivity and learning. METHODS: In experiment 1, systemic injections of 0.00, 0.015, 0.06, and 0.25 mg/kg DMCM were administered before vocalization and tail movements were assessed in response to a gradually incremented shock and radiant heat stimulus. Experiment 2 tested the effects of DMCM on Pavlovian conditioning. DMCM-treated subjects experienced a context paired with an aversive unconditioned stimulus (US) and conditioned freezing was assessed the next day. RESULTS: Experiment 1 showed that DMCM inhibits both a spinal nociceptive reflex (tail-flick to heat) and a supraspinal measure of pain (vocalization to shock). Because these inhibitory effects could reflect a disruption in motor function, experiment 2 employed a remote test based on Pavlovian conditioning. A moderate dose of DMCM undermined learning, implying that the drug decreased the affective impact of the aversive US. CONCLUSIONS: DMCM induces hypoalgesia on a wide range of assays. Furthermore, pharmacologically inducing a negative affective state blocks Pavlovian fear conditioning. It is suggested that DMCM induces a state of panic and that this state inhibits pain.
Subject(s)
Affect/physiology , Carbolines/pharmacology , GABA Agonists/pharmacology , GABA-A Receptor Agonists , Learning/drug effects , Pain/psychology , Animals , Conditioning, Psychological/drug effects , Electroshock , Male , Rats , Rats, Sprague-Dawley , Reaction Time/drug effectsABSTRACT
Considerable animal research suggests that exposure to noxious and nonnoxious fear-inducing stimuli can produce hypoalgesia. Although this effect is thought to generalize across species, only a few studies have examined the pain modulatory effects of nonnoxious fear-eliciting stimuli in humans. The present study examined whether exposure to a series of loud noise bursts would produce a fear-related hypoalgesia in male and female human subjects. Both subjective and physiologic measures (skin conductance level, heart rate) indicated that noise exposure resulted in fear, sympathetic arousal, and decreased pain reactivity in women (n = 20). In contrast, men (n = 20) did not experience fear or physiologic arousal, but reacted with surprise and increased pain reactivity. These findings provide additional evidence that hypoalgesia is mediated by fear and physiologic arousal. Although future studies should directly manipulate surprise, it appears that surprise without fear and physiologic arousal might enhance pain processing.
ABSTRACT
Rats exposed to a few moderately intense (1 mA) shocks subsequently exhibit lower vocalization thresholds to shock and thermal stimuli. They also exhibit facilitated learning in a Pavlovian conditioning paradigm. Together, these results suggest that shock exposure can enhance pain (hyperalgesia). The present study examined the role of the amygdala and bed nucleus of the stria terminalis (BNST), 2 systems that have been implicated in the induction and maintenance of negative affective states. Experiment 1 showed that lesions of the central, but not the basolateral, amygdala eliminate shock-induced hyperalgesia as measured by a decrease in vocalization thresholds to shock. Experiment 2 revealed that central nucleus lesions also prevent shock-induced sensitization of the vocalization response to heat. Anterior, but not posterior, BNST lesions had a similar effect.
Subject(s)
Amygdala/physiopathology , Hyperalgesia/physiopathology , Pain Threshold/physiology , Septal Nuclei/physiopathology , Animals , Brain Mapping , Electroshock , Male , Rats , Reflex, Startle/physiology , Thermosensing/physiologyABSTRACT
Exposure to 3 moderately intense (1-mA) tailshocks has been shown to lower vocalization thresholds to both heat and shock. Previous shock exposure also facilitates the acquisition of conditioned fear as measured by freezing. These observations suggest that shock induces hyperalgesia (enhanced pain). This study explored whether shock-induced hyperalgesia depends on neurons within rostral or caudal portions of the dorsolateral periaqueductal gray (dlPAG). Experiment 1 examined the impact of dlPAG lesions on the acquisition of conditioned fear. Sham-operated rats demonstrated enhanced acquisition after shock exposure; both rostral and caudal lesions eliminated this effect. Experiment 2 showed that tailshock lowered vocalization thresholds to heat in sham-operated but not lesioned subjects. These results suggest that the dlPAG plays a critical role in the production of shock-induced hyperalgesia.
Subject(s)
Conditioning, Classical , Electroshock , Fear , Hot Temperature , Nerve Net/physiology , Pain Threshold/physiology , Periaqueductal Gray/physiology , Animals , Male , Periaqueductal Gray/pathology , Periaqueductal Gray/surgery , Rats , Rats, Sprague-Dawley , Vocalization, AnimalABSTRACT
Exposure to a few moderately intense (1-mA) tailshocks has opposite effects on two measures of pain reactivity in rats. Tail-withdrawal to radiant heat is inhibited (antinociception) while vocalization thresholds are lowered (hyperalgesia) to both heat and shock (King et al., 1996). Prior work indicates that this hyperalgesia represents an unconditioned response and that it enhances the acquisition of both conditioned freezing and an avoidance response to thermal pain. The present experiments begin to explore the neural mechanisms that underlie hyperalgesia. Experiments 1 and 2 demonstrated that hyperalgesia is eliminated by both decerebration and pentobarbital anesthesia. Lesions limited to the frontal pole had a similar effect (Experiment 3). Experiment 4 showed that lesioning the frontal pole also disrupted the acquisition of conditioned fear.
Subject(s)
Pain Threshold/physiology , Prosencephalon/physiology , Animals , Arousal/physiology , Brain Mapping , Electroshock , Fear/physiology , Frontal Lobe/physiology , Male , Nociceptors/physiology , Rats , Rats, Sprague-Dawley , Tail/innervation , Thermosensing/physiologyABSTRACT
Past research indicates that the anticholinergic drug scopolamine disrupts memory and environmentally induced hypoalgesia in rats. The present study examined the impact of the centrally active cholinesterase inhibitor physostigmine, which enhances memory and central cholinergic activity, on brief shock-induced hypoalgesia on the tail-flick test using Sprague-Dawley rats. It is reported that physostigmine (0.1 mg/kg) potentiates the magnitude of this hypoalgesia. Contrary to past research, our results showed that omission of baseline testing did not eliminate hypoalgesia or its potentiation by physostigmine. Similar to its effects on memory, physostigmine (0.04, 0.1, and 0.25 mg/kg) has a nonmonotonic impact on brief shock-induced hypoalgesia; low doses potentiated hypoalgesia (0.1 mg/kg), whereas a high dose (0.25 mg/kg) disrupted it. These results provide further evidence that the cholinergic system indirectly affects pain reactivity by modulating the memory of the aversive event.
Subject(s)
Cholinesterase Inhibitors/pharmacology , Memory/drug effects , Physostigmine/pharmacology , Analgesia , Animals , Cholinesterases/metabolism , Learning/drug effects , Male , Nociceptors/drug effects , Pain , Rats , Rats, Sprague-Dawley , ShockABSTRACT
Shocked rats (Rattus norvegicus) often exhibit longer tail withdrawal latencies to radiant heat, which suggests that exposure to shock reduces pain. But at the same time, rats appear hyperreactive to shock, suggesting than pain is enhanced. Experiment 1 replicated these findings and showed that when tail movement was monitored, shocked rats were less responsive to heat and hyperreactive to shock even when the same behavioral criteria were used. When latency to vocalize was measured, shocked rats appeared hyperreactive to both test stimuli (Experiments 2 and 3). Prior exposure to shock also enhanced the acquisition of conditioned fear in a different context (Experiment 4) and the speed with which rats learned a response to avoid a thermal stimulus (Experiment 5). The results suggest that exposure to shock enhances pain.
Subject(s)
Association Learning , Conditioning, Classical , Fear , Pain Threshold , Reflex, Startle , Thermosensing , Animals , Arousal , Avoidance Learning , Electroshock , Male , Rats , Rats, Sprague-Dawley , Reaction TimeABSTRACT
Pain reactivity is often assessed in rodents by measuring the latency of tail withdrawal from radiant heat (the tail-flick test). Using this test, the authors show that the magnitude of antinociception observed in spinal rats depends on test location; antinociception is observed at, and distal to, where shock is applied, but not at more proximal sites (Experiments 1 & 2). Experiment 3 evaluates the generality of this observation by testing 3 other shock schedules that are known to elicit distinct forms of antinociception. In all but 1 case, the magnitude of antinociception varied as a function of test location. Experiment 4 shows that morphine also has a greater impact at distal test locations. Experiment 5 assessed the impact of tailshock on reactivity to radiant heat applied to the foot. Of the 5 distinct forms of shock-induced antinociception studied, only 2 produce a robust antinociception at this test location.