Effect of a synthetic appeasing pheromone on behavioral, neuroendocrine, immune, and acute-phase perioperative stress responses in dogs.

OBJECTIVE: To study the effects of a synthetic, dog-appeasing pheromone (sDAP) on the behavioral, neuroendocrine, immune, and acute-phase perioperative stress responses in dogs undergoing elective orchiectomy or ovariohysterectomy. DESIGN: Randomized, controlled clinical trial. ANIMALS: 46 dogs housed in animal shelters and undergoing elective orchiectomy or ovariohysterectomy. PROCEDURES: Intensive care unit cages were sprayed with sDAP solution or sham treated with the carrier used in the solution 20 minutes prior to use. Dogs (n = 24 and 22 in the sDAP and sham treatment exposure groups, respectively) were placed in treated cages for 30 minutes before and after surgery. Indicators of stress (ie, alterations in behavioral, neuroendocrine, immune, and acute-phase responses) were evaluated perioperatively. Behavioral response variables, salivary cortisol concentration, WBC count, and serum concentrations of glucose, prolactin, haptoglobin, and C-reactive protein were analyzed. RESULTS: Behavioral response variables and serum prolactin concentration were influenced by sDAP exposure. Dogs exposed to sDAP were more likely to have alertness and visual exploration behaviors after surgery than were dogs exposed to sham treatment. Decreases in serum prolactin concentrations in response to perioperative stress were significantly smaller in dogs exposed to sDAP, compared with findings in dogs exposed to the sham treatment. Variables examined to evaluate the hypothalamic-pituitary-adrenal axis, immune system, and acute-phase responses were unaffected by treatment. CONCLUSIONS AND CLINICAL RELEVANCE: sDAP appeared to affect behavioral and neuroendocrine perioperative stress responses by modification of lactotropic axis activity. Use of sDAP in a clinical setting may improve the recovery and welfare of dogs undergoing surgery.

An analysis of plasma reveals proteins in the acute phase response pathway to be candidate diagnostic biomarkers for depression.

Globally, depression is one of the most serious debilitating psychiatric mental disorders. In this study, we validated the expression levels of fibrinogen alpha (FGA), fibrinogen beta (FGB), fibrinogen gamma (FGG), Complement factor B (CFB) and serpin family D member 1(SERPIND1) in the acute phase response signaling pathway in plasma samples using enzyme-linked immunosorbent assay (ELISA).Then illuminate the roles of FGA, FGB, FGG, CFB, SERPIND1 in depression using microarray data. Gene expression dataset GSE98793 was downloaded from the Gene Expression Omnibus database. There were 128 whole blood samples included 64 patients with major depressed patients and 64 healthy controls. Differentially expressed genes (DEGs) were identified, and then protein-protein interaction (PPI) network was constructed to screen crucial genes associated with FGA, FGB, FGG, CFB and SERPIND1. Moreover, gene ontology (GO) biological processes analyses was performed. The ELISA data showed that the expression levels of FGA, FGB, FGG, CFB and SERPIND1 were up-regulated in depressed patients. The enriched GO terms were predominantly associated with the biological processes including more genes were inflammation related. The PPI network was found these five genes interacted with 11 genes. FGA, FGB, FGG, CFB and SERPIND1 may be important in the pathogenesis of depression.

A biological substrate for somatoform disorders: importance of pathophysiology.

Somatoform disorders are troubling to both patients and physicians. The diagnosis regrettably relies on the presence of subjective distress in the absence of objective findings. As a result, there is always the possibility that a diagnosis will be "missed." There is a clear underlying physiology of distress, which implies that there is a two-way street--both psychosomatic and somatopsychic in terms of production and experience of somatoform symptoms. Studies on communication pathways from the immune system to the brain provide exciting new information on the pathophysiology of inflammation-associated symptoms.

Suppression of the acute-phase response as a biological mechanism for the placebo effect.

The idea that inert substances such as sugar pills can have powerful therapeutic effects--the so-called 'placebo effect'--has been widely accepted by most medical researchers since the 1950s. Today there is increasing scepticism about the reality of the placebo effect. This debate has been too simplistic; rather than asking whether or not the placebo effect exists, as researchers have done up to now, we should be more precise, and ask which medical conditions (if any) are placebo-responsive. There is evidence that pain, swelling, stomach ulcers, depression, and anxiety are all placebo-responsive. These conditions have all been linked, to a greater or lesser extent, with activation of the acute-phase response (the innate immune response). The placebo effect may therefore be mediated by alteration of one or more components of the acute-phase response. The candidates for such biochemical mediators would need to alter the synthesis, activation, receptor-binding or signalling mechanisms of inflammation, sickness behaviour and other aspects of innate immunity. This hypothesis is consistent with current data suggesting that placebos work by triggering the release of endorphins. The hypothesis would be falsified if it were found that other medical conditions, not involving the activation of the acute-phase response, were nonetheless alleviated by placebos.

Elevated levels of acute phase plasma proteins in major depression.

Levels of acute phase and other plasma proteins were measured in 21 men with major depression, 28 men with alcohol dependence, and 12 men who acted as controls. The depressed men had significantly elevated levels of the acute phase proteins, haptoglobin and alpha-1-antichymotrypsin, and of immunoglobulin G. The elevations in haptoglobin and alpha-1-antichymotrypsin were highly correlated with each other, and were correlated with the severity of depression and negatively correlated with the thyroid stimulating hormone response to thyrotropin. The alcoholic men had elevated haptoglobin levels, but significantly decreased levels of immunoglobulin G. These findings provide further evidence for an inflammatory response during depression.

The long term acute phase-like responses that follow acute stressor exposure are blocked by alpha-melanocyte stimulating hormone.

Both intracerebroventricular (i.c.v.) IL-1beta and exposure to inescapable tail shock (IS) activate acute phase responses (APRs) that include increases in core body temperature (CBT), increases in hypothalamic-pituitary-adrenal activity, decreases in carrier proteins such as corticosterone binding globulin (CBG), aphagia and adipsia. A variety of data suggested that stressors produce APRs by inducing brain IL-1beta. The current series of studies further explored this possibility by determining whether the functional IL-1beta antagonist, alpha-melanocyte-stimulating hormone (alpha-MSH(1-13)), would block IS-induced APRs. Immediately following i.c.v. alpha-MSH(1-13) administration, rats were exposed to a single session of 100, 5 s, 1.6 mA ISs, or control treatment (home cage control). alpha-MSH(1-13) blocked IS-induced increased CBT, increased plasma corticosterone (CORT), decreased CBG, aphagia and adipsia 24 h after IS. The inhibitory effects of alpha-MSH(1-13) were shown not to be a consequence of alpha-MSH(1-13) producing its actions 24 h after its administration because alpha-MSH(1-13) given 24 h before IS did not block IS-induced increased CBT and CORT during IS. Additionally, alpha-MSH(1-13), given 24 h before IS, had no effect on increased CBT, increased CORT, decreased CBG, adipsia, or aphagia 24 h after IS. These data provide support for a specific mode of action for i.c.v. alpha-MSH(1-13), namely blockade of APRs with no impact on acute hyperthermia or increased levels of CORT produced during IS.

Increased serum interleukin-1-receptor-antagonist concentrations in major depression.

Recently, it has been shown that major depression may be accompanied by an increased production of interleukin-1 beta (IL-1 beta), an acute phase (AP) response and simultaneous signs of activation and suppression of cell-mediated immunity. The interleukin-1-receptor antagonist (IL-1-rA) is released in vivo during an AP response and serum levels are increased in many immune disorders. The release of IL-1-rA may limit the pro-inflammatory effects of IL-1. This study has been carried out to examine serum IL-1-Ra in 68 depressed subjects (21 minor, 25 simple major and 22 melancholic subjects) vs. 22 normal controls. Depressed subjects showed significantly higher serum IL-1-rA concentrations than healthy controls. 29% of all depressed subjects had serum IL-1-rA levels higher than the mean value +2 standard deviations of normal controls; 44% depressed subjects had IL-1-rA values greater than 0.215 ng/ml with a specificity of 90%. In depressed subjects, there was a significant and positive relationship between serum IL-1-rA and severity of illness. In depression, there were no significant relationships between serum IL-1-rA concentrations and indicants of hypothalamic-pituitary-adrenal (HPA)-axis activity, such as 24-h urinary cortisol and postdexamethasone cortisol values. Women had significantly higher serum IL-1-rA levels than men. The findings support the thesis that depression is accompanied by an immune-inflammatory response.

Higher alpha 1-antitrypsin, haptoglobin, ceruloplasmin and lower retinol binding protein plasma levels during depression: further evidence for the existence of an inflammatory response during that illness.

Recently, a few reports have shown that severe depression may be associated with higher levels of positive acute phase proteins (APPs), such as haptoglobin (Hp), alpha 1-acid glycoprotein (alpha 1S) and lower levels of negative APPs (visceral proteins), such as albumin (Alb) and transferrin (Tf). In order to reassess whether depression is related to alterations in the expression of plasma APP concentrations, we measured in 84 normal controls and depressed inpatients positive APPs such as Hp, alpha 1-antitrypsin (alpha 1AT), hemopexin (Hpx), ceruloplasmin (Cp), complement component C3C and one visceral protein, i.e., retinol binding protein (RBP). We found increased plasma concentrations of Hp, alpha 1AT, and Cp in major depressed subjects as compared with healthy controls, with minor depressives exhibiting an intermediate position. RBP was significantly lower in minor and major depressives than in normal controls. The disorders in these proteins were rather sensitive (62%) for major depression, with a specificity equalling 96%. Our findings are compatible with the hypothesis that major depression may be accompanied by inflammatory changes with higher levels of positive APPs (i.e., alpha 1AT, Hp, Cp, alpha 1S) and lower levels of visceral proteins (i.e., RBP, Tf, Alb).

Modification of body temperature and sleep state using behavioral conditioning.

Previous research has demonstrated the conditionability of events within the acute-phase response. This study examined whether two such responses, fever and sleep alterations, were conditionable in the rat during the dark photoperiod. The experimental animals were administered a novel saccharin solution as the conditioned stimulus (CS) in conjunction with lipopolysaccharide as the unconditioned stimulus (UCS). This group displayed significantly higher body temperatures than controls upon saccharin representation, 7 days after the original CS-UCS pairing. The experimental animals additionally displayed a conditioned increase in slow wave sleep (SWS); however, the LPS-induced reduction in rapid eye movement (REM) sleep was unable to be reenlisted. Similar to the acute-response, the conditioned alteration in SWS appeared to be due to an increase in episode frequency, rather than duration. These results suggest that the multiple acute-phase events may be simultaneously conditionable, producing an optimum environment for pathogen elimination.

Responses of guinea pig pups during isolation in a novel environment may represent stress-induced sickness behaviors.

When guinea pig pups are isolated in a novel environment, they show an initial active phase of behavioral responsiveness characterized by vocalizations and locomotor activity. One earlier study found that after about an hour, pups began to exhibit a second, passive stage of responsiveness marked by a crouched stance, eye-closing, and extensive piloerection. The present experiments tested the hypothesis that the responses during the second, passive stage result from the isolation experience activating pathways underlying the acute phase response, i.e., that behaviors of the second stage represent "stress-induced sickness behaviors". We found the following: (1) the passive stage did not emerge if pups remained with the mother during exposure to a novel cage; (2) injection of lipopolysaccharide, which induces an acute phase response, also led pups to exhibit crouching, eye-closing, and piloerection; and, (3) isolation in the novel cage produced a rise in rectal temperature, but did not affect peripheral or central levels of interleukin-1beta (IL-1beta)-immunoreactivity. Overall, these results are consistent with the notion that stress-induced sickness behaviors can account for some of the behaviors of isolated guinea pig pups, though if this is the case, cytokines other than IL-1beta appear to be involved.

Psychomotor retardation, anorexia, weight loss, sleep disturbances, and loss of energy: psychopathological correlates of hyperhaptoglobinemia during major depression.

Recently, we have established that major depression is characterized by hyperhaptoglobinemia, which may be regarded as an index of an "acute" phase response in that illness. The present study investigates the psychopathological correlates of increased plasma concentrations of haptoglobin (Hp) in major depression. To this end, the authors studied the Hp levels in relation to depressive items of the Structured Clinical Interview for DSM-III (SCID) and the Hamilton Rating Scale for Depression (HRSD) in 90 depressed subjects. There was a significant positive relationship between the SCID symptoms anorexia/weight loss, sleep, and psychomotor disorders and Hp plasma concentrations. Hp plasma levels were significantly and positively correlated with overall severity of illness (HRSD). The HRSD symptom correlates of higher Hp levels were loss of interest, middle insomnia, and psychomotor retardation. Up to 31.4% of the variance in Hp plasma values could be explained by psychomotor disorders, anorexia, weight loss, middle insomnia, and less diurnal variation of mood. It is suggested that hyperhaptoglobinemia, as an index of an "acute" phase response in major depression, is related to the somatic dimension of depressive illness.

Paradoxical conditioning of the plasma copper and corticosterone responses to bacterial endotoxin.

The cascade of physiologic mechanisms in response to infection, the acute phase response, is recognized as having a major role in host defense. Two such responses are an increase in plasma copper and activation of the hypothalamic-pituitary-adrenal axis, which are consistently reported to occur during bacterial infection. We aimed to determine whether the alterations in plasma copper and corticosterone were conditionable using the conditioned taste aversion paradigm. The regime involved the pairing of a novel-tasting saccharine solution (the conditioned stimulus) with lipopolysaccharide (the unconditioned stimulus). Seven days after the initial pairing of these stimuli (the test day), the saccharine solution was represented. Animals exposed to this condition displayed a significant decrease in plasma copper levels. In addition, these rats experienced a reduction in plasma corticosterone that was time dependent. Paradoxically, the conditioned response of both these variables were in a direction contrary to that reported during bacterial infection. These results suggest that some acute phase responses may condition as a rebound response, or in an opposing trend to that occurring as the initial reaction.

Natural variations in the stress and acute phase responses of cattle.

Activation of the innate immune system and acute phase response (APR) results in several responses that include fever, metabolic adaptations and changes in behavior. The APR can be modulated by many factors, with stress being the most common. An elevation of stress hormones for a short duration of time can be beneficial. However, elevation of stress hormones repeatedly or for an extended duration of time can be detrimental to the overall health and well-being of animals. The stress and APR responses can also be modulated by naturally-occurring variations, such as breed, gender, and temperament. These three natural variations modulate both of these responses, and can therefore modulate the ability of an animal to recover from a stressor or infection. Understanding that cattle have different immunological responses, based on naturally occurring variations such as these, may be the foundation of new studies on how to effectively manage cattle so that health is optimized and production is benefited.

Serotonin-immune interactions in major depression: lower serum tryptophan as a marker of an immune-inflammatory response.

Serum total tryptophan and the five competing amino acids (CAA), i.e., valine, leucine, tyrosine, phenylalanine, and isoleucine were determined in 35 major depressed subjects of whom 27 with treatment resistant depression (TRD), and 15 normal controls. Twenty-five of the depressed subjects had repeated measurements of the amino acids both before and after antidepressive treatment. The following immune-inflammatory variables were assayed in the above subjects: serum zinc (Zn), total serum protein (TSP), albumin (Alb), transferrin (Tf), iron (Fe), high-density lipoprotein cholesterol (HDL-C), number of peripheral blood leukocytes, and the CD4+/CD8+ T cell (T-helper/T-suppressor) ratio. Serum tryptophan and the tryptophan/CAA ratio were significantly lower in major depressed subjects than in normal controls. The tryptophan/CAA ratio was significantly lower in patients with TRD than in patients without TRD and normal controls. There were no significant alterations in any of the amino acids upon successful therapy. There were significant correlations between serum tryptophan and serum Zn, TSP, Alb, Tf, Fe, and HDL-C (all positive), and number of leukocytes and the CD4+/CD8+ T-cell ratio (all negative). The tryptophan/CAA ratio was significantly and negatively related to the number of leukocytes and the CD4+/CD8+ T-cell ratio. The results suggest that (a) TRD is characterized by lower availability of serum tryptophan; (b) the availability of tryptophan may remain decreased despite clinical recovery; and (c) the lower availability of tryptophan is probably a marker of the immune-inflammatory response during major depression.