Vasopressin V1B Receptor Antagonists as Potential Antidepressants

Accumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-vasopressin (AVP) is one of the primary factors in HPA axis regulation under stress situations, and AVP and its receptor subtype (V_1B receptor) play a pivotal role in HPA axis abnormalities observed in depression. Based on this hypothesis, several non-peptide V_1B receptor antagonists have been synthesized, and the efficacies of some V_1B receptor antagonists have been investigated in both animals and humans. V_1B receptor antagonists exert antidepressant-like effects in several animal models at doses that attenuate the hyperactivity of the HPA axis, and some of their detailed mechanisms have been delineated. These results obtained in animal models were, at least partly, reproduced in clinical trials. At least 2 V_1B receptor antagonists (TS-121 and ABT-436) showed tendencies to reduce the depression scores of patients with major depressive disorder at doses that attenuate HPA axis hyperactivity or block the pituitary V_1B receptor. Importantly, TS-121 showed a clearer efficacy for patients with higher basal cortisol levels than for those with lower basal cortisol levels, which was consistent with the hypothesis that V_1B receptor antagonists may be more effective for patients with HPA axis hyperactivity. Therefore, V_1B receptor antagonists are promising approaches for the treatment of depression involving HPA axis impairment such as depression.     

Flavonoids of St. John's Wort reduce HPA axis function in the rat

A common biological alteration in patients with major depression is the activation of the hypothalamic-pituitary-adrenal (HPA) axis, manifested as hypersecretion of adrenocorticotropic hormone (ACTH) and cortisol. The hyperactivity of the HPA axis in depressed patients can be corrected during clinically effective therapy with standard antidepressant drugs such as imipramine, indicating that the HPA axis may be an important target for antidepressant action. We previously showed that a methanolic extract of St. John's Wort (SJW) and hypericin, one of its active constituents, both have delayed effects on the expression of genes that are involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis , whereas the phloroglucinol derivative hyperforin was inactive in the same model . Since flavonoids of SJW are also discussed as active constituents it was of interest to determine whether these compounds can modulate HPA axis function. Imipramine (15 mg/kg), hypericin (0.2 mg/kg), hyperoside (0.6 mg/kg), isoquercitrin (0.6 mg/kg) and miquelianin (0.6 mg/kg) given daily by gavage for two weeks significantly down-regulated circulating plasma levels of ACTH and corticosterone by 40 - 70 %. However, none of the compounds tested had an effect on plasma ACTH and corticosterone levels after chronic treatment (daily gavage for 8 weeks). Our data suggest that besides hypericin, flavonoids of SJW play an important role in the modulation of HPA axis function. Furthermore, the results support the hypothesis that flavonoids are involved in the antidepressant effects of SJW.     

Exogenous cortisol acutely influences motivated decision making in healthy young men

Background

The glucocorticoid (GC) hormone cortisol is the end product of the hypothalamic–pituitary–adrenal axis (HPA axis). Acute psychological stress increases HPA activity and GC release. In humans, chronic disturbances in HPA activity have been observed in affective disorders and in addictive behaviour. Recent research indicates that acute effects of GCs may be anxiolytic and increase reward sensitivity. Furthermore, cortisol acutely influences early cognitive processing of emotional stimuli.

Methods

In order to extend such findings to more complex emotional-cognitive behaviour, the present study tested acute effects of 40 mg cortisol on motivated decision making in 30 healthy young men.

Results

Results showed that cortisol indeed increased risky decision making, as predicted. This effect occurred for decisions where making a risky choice could potentially yield a big reward. These results are discussed with respect to currently proposed mechanisms for cortisol’s potential anxiolytic effect and GCs’ involvement in reward systems.     

Corticosteroid-serotonin interactions in depression: a review of the human evidence

Rationale It has been suggested that corticosteroid-serotonin interactions are central to the pathophysiology of depression. These interactions have been investigated in healthy and depressed humans, primarily using neuroendocrine techniques.Objectives To review the evidence regarding the nature of these interactions in healthy and depressed humans.Methods Electronic searches were performed for relevant papers, employing MEDLINE and Web of Science. To focus the review, we selected only those articles involving (i) assessment of serotonergic function following experimental manipulation of the HPA axis in healthy volunteers; and (ii) assessment of both serotonergic and HPA axis function in clinically depressed subjects.Results Pre-treatment with hydrocortisone, both acutely and sub-acutely attenuates the GH response to GHRH in healthy subjects. This complicates the interpretation of 5-HT neuroendocrine studies employing GH output as a measure. In depression there is evidence that reduced availability of l-tryptophan impairs HPA axis feedback. There is also evidence that depressed and healthy subjects may adapt differently both to low tryptophan and hypercortisolaemic challenges. There is no consistent evidence of a simple relationship between HPA axis function and 5-HT function in depression.Conclusions The putative reduction in central 5-HT function has not been shown to be a direct consequence of hypercortisolaemia. Rather, the 5-HT system and HPA axis have complex inter-relationships. Challenges to either system, such as stress or reduced dietary tryptophan, may perturb the other and subjects vulnerable to depression may fail to adapt to such challenges.     

Neural Correlates of the Cortisol Awakening Response in Humans

The cortisol rise after awakening (cortisol awakening response, CAR) is a core biomarker of hypothalamic-pituitary-adrenal (HPA) axis regulation related to psychosocial stress and stress-related psychiatric disorders. However, the neural regulation of the CAR has not been examined in humans. Here, we studied neural regulation related to the CAR in a sample of 25 healthy human participants using an established psychosocial stress paradigm together with multimodal functional and structural (voxel-based morphometry) magnetic resonance imaging. Across subjects, a smaller CAR was associated with reduced grey matter volume and increased stress-related brain activity in the perigenual ACC, a region which inhibits HPA axis activity during stress that is implicated in risk mechanisms and pathophysiology of stress-related mental diseases. Moreover, functional connectivity between the perigenual ACC and the hypothalamus, the primary controller of HPA axis activity, was associated with the CAR. Our findings provide support for a role of the perigenual ACC in regulating the CAR in humans and may aid future research on the pathophysiology of stress-related illnesses, such as depression, and environmental risk for illnesses such as schizophrenia.     

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

Alcohol withdrawal is associated with hypothalamic–pituitary–adrenal (HPA) axis dysfunction. The FKBP5 gene codes for a co-chaperone, FK506-binding protein 5, that exerts negative feedback on HPA axis function. This study aimed to examine the effects of single-nucleotide polymorphisms (SNPs) of the FKBP5 gene in humans and the effect of Fkbp5 gene deletion in mice on alcohol withdrawal severity. We genotyped six FKBP5 SNPs (rs3800373, rs9296158, rs3777747, rs9380524, rs1360780, and rs9470080) in 399 alcohol-dependent inpatients with alcohol consumption 48 h before admission and recorded scores from the Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar). Fkbp5 gene knockout (KO) and wild-type (WT) mice were assessed for alcohol withdrawal using handling-induced convulsions (HICs) following both acute and chronic alcohol exposure. We found the minor alleles of rs3800373 (G), rs9296158 (A), rs1360780 (T), and rs9470080 (T) were significantly associated with lower CIWA-Ar scores whereas the minor alleles of rs3777747 (G) and rs9380524 (A) were associated with higher scores. The haplotype-based analyses also showed an association with alcohol withdrawal severity. Fkbp5 KO mice showed significantly greater HICs during withdrawal from chronic alcohol exposure compared with WT controls. This study is the first to show a genetic effect of FKBP5 on the severity of alcohol withdrawal syndrome. In mice, the absence of the Fkbp5 gene enhances sensitivity to alcohol withdrawal. We suggest that FKBP5 variants may trigger different adaptive changes in HPA axis regulation during alcohol withdrawal with concomitant effects on withdrawal severity.     

Hyperforin-containing extracts of St John's wort fail to alter gene transcription in brain areas involved in HPA axis control in a long-term treatment regimen in rats.

We previously showed that a methanolic extract of St John's wort (SJW) (Hypericum) and hypericin, one of its active constituents, both have delayed regulation of genes that are involved in the control of the hypothalamic-pituitary-adrenal (HPA) axis. Hyperforin, another constituent of SJW, is active in vitro and has been proposed to be the active constituent for therapeutic efficacy in depression. We therefore examined if hyperforin has delayed effects on HPA axis control centers similar to those of Hypericum and hypericin. We used in situ hybridization histochemistry to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) oral administration of two hyperforin preparations, fluoxetine (positive control), and haloperidol (negative control) on the expression of genes involved in the regulation of the HPA axis. Fluoxetine (10 mg/kg) given daily for 8 weeks, but not 2 weeks, significantly decreased levels of corticotropin-releasing hormone (CRH) mRNA by 22% in the paraventricular nucleus (PVN) of the hypothalamus and tyrosine hydroxylase (TH) mRNA by 23% in the locus coeruleus. Fluoxetine increased levels of mineralocorticoid (MR) (17%), glucocorticoid (GR) (18%), and 5-HT(1A) receptor (21%) mRNAs in the hippocampus at 8, but not 2, weeks. Comparable to haloperidol (1 mg/kg), neither the hyperforin-rich CO(2) extract (27 mg/kg) nor hyperforin-trimethoxybenzoate (8 mg/kg) altered mRNA levels in brain structures relevant for HPA axis control at either time point. These data suggest that hyperforin and hyperforin derivatives are not involved in the regulation of genes that control HPA axis function.     

The effects of antidepressants on the hypothalamic-pituitary-adrenal axis

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been found in some psychiatric disorders, especially in older patients with severe depression. Altered feedback inhibition, as demonstrated by increased circulating cortisol and nonsuppresssion of cortisol following administration of dexamethasone, may be to blame. Two glucocorticoid receptors control the HPA axis, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). MR regulates normal HPA fluctuations and the GR regulates in times of stress. Long-term antidepressant treatment in humans has been shown to upregulate both GR and MR in the brain, whereas short-term treatment has been shown to downregulate GR and MR. After 6-9 weeks of treatment GR function returns to normal, and the MR stays upregulated. Chronic antidepressant treatment in rodents has been shown to reduce HPA activity, even in the absence of GR or MR upregulation. These effects of antidepressants on HPA regulation may be attributed in part to regulation of the multidrug resistance protein transporter, P-glycoprotein. Finding relationships between antidepressant action and HPA regulation leads to the conclusion that the disruption of the HPA may be more a contributing factor to depression than other biological abnormalities.     

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shock-mediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.     

HPA function in adolescence: role of sex hormones in its regulation and the enduring consequences of exposure to stressors

The hypothalamic-pituitary-adrenal (HPA) axis is one of the physiological systems involved in coping with stressors. There are functional shifts in the HPA axis and its regulation by sex hormones over the lifespan that allow the animal to meet the challenges of the internal and external environment that are specific to each stage of development. Sex differences in HPA function emerge over adolescence, a phenomenon reflecting the concomitant initiation of regulatory effects of sex hormones. The focus of this review is recent research on differences between adolescents and adults in HPA function and the enduring effects of exposure to stressors in adolescence. During adolescence, HPA function is characterized by a prolonged activation in response to stressors compared to adulthood, which may render ongoing development of the brain vulnerable. Although research has been scarce, there is a growing evidence that exposure to stressors in adolescence may alter behavioural responses to drugs and cognitive performance in adulthood. However, the effects reported appear to be stressor-specific and sex-specific. Such research may contribute toward understanding the increased risk for drug abuse and psychopathology that occurs over adolescence in people.     

Influence of psychological variables on the activity of the hypothalamic-pituitary-adrenal axis

Psychobiology is the discipline that attempts to integrate the impact of environmental and psychological variables on biological systems. This paper focuses on the psychobiology of the hypothalamic-pituitary-adrenal (HPA) axis and illustrates several processes that influence the response of the HPA axis. The interaction of the developing rodent or primate with their primary care giver has permanent long-term effects on the HPA axis. Manipulations that alter maternal behavior during critical periods of development permanently modify the HPA axis. The HPA axis can be programmed to be hypo-responsive or hyper-responsive as a function of time and length of maternal separation. In the adult organism, the HPA response to stress is highly dependent on specific psychological factors such as control, predictability, and feedback. In primates, social variables have been shown to diminish or exacerbate the HPA stress response. During the post-natal period of development, the mother appears to actively inhibit the pups' HPA axis. Different aspects of maternal behavior regulate different components of the HPA system.     

Plasticity of Presynaptic and Postsynaptic Serotonin 1A Receptors in an Animal Model of Epilepsy-Associated Depression

Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients'' quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo–pituitary–adrenocortical (HPA) axis and/or diminished raphe–hippocampal serotonergic transmission. We examined possible involvement of presynaptic and postsynaptic serotonin 1A (5-HT1A) receptors in epilepsy-associated depression. Based on their performance in the forced swim test (FST), post-SE animals were classified as those with moderate and severe depressive impairments. In moderately impaired rats, the activity of the HPA axis (examined using plasma corticosterone radioimmunoassay) was higher than in naive subjects, but the functional capacity of presynaptic 5-HT1A receptors (measured in raphe using autoradiography) remained unaltered. In severely depressed animals, both the activity of the HPA axis and the function of presynaptic 5-HT1A receptors were increased as compared with naive and moderately depressed rats. Pharmacological uncoupling of the HPA axis from raphe nucleus exerted antidepressant effects in severely impaired rats, but did not modify behavior in both naive and moderately depressed animals. Further, the function of postsynaptic 5-HT1A receptors was diminished in the hippocampus of post-SE rats. Pharmacological activation of postsynaptic 5-HT1A receptors improved depressive deficits in epileptic animals. We suggest that under the conditions of chronic epilepsy, excessively hyperactive HPA axis activates presynaptic 5-HT1A receptors, thus shifting the regulation of serotonin release in favor of autoinhibition. Downregulation of postsynaptic 5-HT1A receptors may further exacerbate the severity of epilepsy-associated depression.     

Depression and alterations in hypothalamic–pituitary–adrenal and hypothalamic–pituitary–thyroid axis function in male abstinent methamphetamine abusers

The present study was to investigate depression and alterations in the hypothalamic–pituitary–adrenal (HPA) and hypothalamic–pituitary–thyroid (HPT) axis function in methamphetamine (METH) abusers after abstinence. Depression was assessed using the 13‐item Beck Depression Inventory (BDI‐13) scale; blood samples from in‐patients who were METH abusers and age‐matched and sex‐matched healthy controls were collected. The demographic characteristics and history of METH abuse also was assessed. We found that serum levels of adrenocorticotropic hormone (ACTH) and thyroxine were increased; and serum levels of cortisol, triiodothyronine, and thyroid‐stimulating hormone were decreased; and the BDI score was higher in METH abusers compared with control. In addition, there was no correlation between the BDI‐13 score and any of hormones of HPA and HPT axis was found. Particularly, we found abnormally higher ACTH level and mismatched with lower cortisol level in abstinent METH abusers. These results indicate that METH abusers and that their HPA and HPT functions are all altered after abstinence. Chronically using METH may destroy the regulatory function of the HPA axis, especially the feedback regulation of cortisol to ACTH. Copyright © 2013 John Wiley & Sons, Ltd.     

Contrasting effects of citalopram and reboxetine on waking salivary cortisol

Rationale. Acute administration of antidepressants which potentiate serotonin (5-HT) and noradrenaline (NA) function stimulates the hypothalamic-pituitary-adrenal (HPA) axis and increases salivary free cortisol in healthy subjects. The effects of repeated antidepressant administration have been less studied, but the ability of such treatment to modulate HPA axis activity may be relevant to therapeutic effects. Objective. The objective of the study was to assess the effect of short-term treatment with two different antidepressant medications on HPA axis activity. Methods. We studied the effect of 6-day treatment with the selective serotonin re-uptake inhibitor (SSRI) citalopram (20 mg daily) and the selective noradrenaline re-uptake inhibitor, reboxetine (8 mg daily), on diurnal salivary cortisol in a parallel group, placebo-controlled, double-blind design. Results. Citalopram significantly enhanced the increase in salivary cortisol produced by waking, while the effect of reboxetine treatment was indistinguishable from placebo. There was no change in basal salivary cortisol levels sampled in a standard pattern throughout the day. Conclusions. Short-term treatment with citalopram and reboxetine produced strikingly different effects on waking salivary cortisol, arguing against a common effect of antidepressant drugs on HPA axis function. Waking salivary cortisol may be a more reliable means of assessing the effects of antidepressant treatment on the HPA axis than a standard regime of basal salivary sampling. Electronic Publication     

Radiolabeled glucocorticoids as molecular probes for imaging brain glucocorticoid receptors by means of positron emission tomography (PET)

Over the last two decades, numerous attempts have been made to develop (11)C- and (18)F-labeled radiotracers in order to study glucocorticoid receptor (GR)-mediated abnormalities of the hypothalamus-pituitary-adrenocortical (HPA) axis function and regulation in vivo by means of positron emission tomography (PET). The present review addresses the research efforts dealing with the design, radiosynthesis and radiopharmacological evaluation of PET radiotracers for brain GR imaging. The underlying problems such as metabolic instability, insufficient blood-brain-barrier penetration and/or high non-specific binding will be discussed.     

Overnight metyrapone and combined dexamethasone/metyrapone tests in post-traumatic stress disorder: preliminary findings.

Using overnight metyrapone and combined dexamethasone/metyrapone tests, hypothalamic-pituitary-adrenocortical (HPA) axis feedback regulation was characterised in 10 patients with post-traumatic stress disorder (PTSD) and 10 matched healthy comparison subjects. Significant treatment effects of both metyrapone and the combination of dexamethasone and metyrapone were observed for adrenocorticotropic hormone (ACTH), 11-deoxycortisol (11-DOC) and cortisol, but no differences between patients and comparison subjects emerged. Dose-response studies using metyrapone and glucocorticoid agonists are needed to further investigate HPA axis regulation in PTSD.     

Brain nitric oxide synthases in the interleukin-1β-induced activation of hypothalamic-pituitary-adrenal axis

BackgroundInterleukin-1β (IL-1β), the major cytokine involved in activation of hypothalamic-pituitary-adrenal (HPA) axis modulates both central and peripheral components regulating HPA activity. The role of nitric oxide (NO) generated by neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) in brain structures involved in HPA axis regulation has not been elucidated. The aim of the study was to assess the receptor selectivity of IL-1β stimulatory action on HPA axis and to determine the involvement of nNOS and iNOS in this stimulation.MethodsExperiments were performed on male Wistar rats which were injected intraperitoneally (ip) with IL-1β (5 μg/kg) or IL-1 receptor antagonist (IL-1ra) (50 μg/kg or 100 μg/kg) 15 min before IL-1β. Rats were sacrificed by rapid decapitation 1, 2 or 3 h after IL-1β administration. Trunk blood for ACTH, corticosterone and IL-1β determinations was collected and prefrontal cortex, hippocampus and hypothalamus were excised and snap frozen. Western blot analyses were performed and IL-1β, nNOS and iNOS protein were determined in brain structures samples.ResultsIL-1β significantly increased plasma ACTH, corticosterone and IL-1β levels during 2 h after ip administration. IL-1 receptor antagonist was able to abolish the stimulatory effect of IL-1β on plasma ACTH and corticosterone levels and significantly, but not totally, reduced plasma IL-1β level. The role of NO in prefrontal cortex, hippocampus and hypothalamus in the IL-1β-induced HPA axis activity alterations was determined by measuring the changes in nNOS and iNOS levels. The highest level of both izoenzymes 1 h following IL-1β administration decreased in a regular, parallel manner 2 and 3 h later, approaching control values. These changes were almost totally prevented by pretreatment with IL-1 receptor antagonist. In the hypothalamus the IL-1β-induced initial significant increase of nNOS regularly decreased in a modest rate and remained at significant higher level compared to control values. By contrast, iNOS level gradually increased 2 and 3 h after IL-1β administration in a significant time-dependent manner. The changes in both NOS izoenzyme levels in hypothalamus were suppressed by pretreatment with IL-1 receptor antagonist. Results also show that a regular and parallel decrease of nNOS in the hypothalamus and prefrontal cortex are parallel in time and magnitude to respective fall in plasma IL-1β and ACTH levels.ConclusionThe present study suggests that the IL-1β-induced transient stimulation of HPA axis activity is parallel in time and magnitude to the respective changes of nNOS in hypothalamus and prefrontal cortex, the brain structures involved in regulation of HPA axis activity.     

Therapeutic implications of HPA axis abnormalities in Alzheimer's disease: review and update

The adaptive and maladaptive roles of the hypothalamic-pituitary-adrenal (HPA) axis in stressful conditions and in disorders such as major depression, posttraumatic stress disorder, and Cushing's syndrome, have been the subject of substantial, ongoing study. In particular, HPA disturbances have been associated with memory impairments, and hypercortisolemic conditions with atrophy of the hippocampus, a limbic structure closely associated with declarative memory. Recent discoveries support a more complicated picture of HPA axis function and pathology in acquiring, retrieving, and consolidating new memories. These findings include: the existence of an 'inverted U-shaped relationship" between stimulation of brain glucocorticoid receptors and memory performance; that distinct areas of the hippocampus have been found to respond differently to cortisol stimulation; and that hippocampal atrophy has been found to be potentially reversible in some conditions, although whether such atrophy is a cause or effect of these pathological conditions is currently unclear. More longitudinal studies of HPA axis function in aging normal individuals, those with mild cognitive impairment,and individuals with Alzheimer' disease, examining pertinent variables such as APOEe-4 status, are needed to help clarify these new findings. Antiglucocorticoid agents appear to have therapeutic value in particular conditions. These results are relevant for understanding and treating memory dysfunction in individuals with Alzheimer's disease, a disorder prominently and invariably characterized by early hippocampal lesions and memory impairment. Given the burden of this disease, we feel it timely to encourage controlled trials of antiglucocorticoid agents in the treatment of mild cognitive impairment and Alzheimers disease.     

Interactions of orphanin FQ/nociceptin (OFQ/N) system with immune system factors and hypothalamic–pituitary–adrenal (HPA) axis

BackgroundBrain–immune system interactions and neurohormonal changes which are induced by psychophysiological factors are growing areas of scientific interest. Central (CNS) and autonomic nervous-endocrine-immune system pathways are connected with a number of behavioral and physiological factors which may be linked to disease susceptibility and progression.MethodsIn this paper, influence of orphanin FQ/nociceptin receptor (OFQ/N) on the hypothalamic–pituitary–adrenal (HPA) axis and their influence on the immunological system was reviewed.ConclusionsThe neuroendocrine system, in particular the hypothalamic–pituitary–adrenal (HPA) axis, is closely connected with the cytokines. HPA axis activation by cytokines, via the release of glucocorticoids has, in turn, been found to play a critical role in restraining and shaping immune responses. Investigation of the OFQ/N system and G-proteins suggests a role for this receptor as a down-regulator of cytokine, chemokine and chemokine receptor expression.