Bradykinin actions in the central nervous system: historical overview and psychiatric implications.

Bradykinin (BK), a well-studied mediator of physiological and pathological processes in the peripheral system, has garnered less attention regarding its function in the central nervous system, particularly in behavioural regulation. This review delves into the historical progression of research focused on the behavioural effects of BK and other drugs that act via similar mechanisms to provide new insights into the pathophysiology and pharmacotherapy of psychiatric disorders. Evidence from experiments with animal models indicates that BK modulates defensive reactions associated with panic symptoms and the response to acute stressors.

Antipanic-like effect of esketamine and buprenorphine in rats exposed to acute hypoxia.

The antidepressant effect of ketamine has been widely acknowledged and the use of one of its enantiomers, S-ketamine (esketamine), has recently been approved for the clinical management of treatment-resistant depression. As with ketamine, the non-selective opioid receptor-interacting drug buprenorphine is reported to have antidepressant and anxiolytic properties in humans and rodents. Given the fact that antidepressant drugs are also first line treatment for panic disorder, it is surprising that the potential panicolytic effect of these compounds has been scarcely (ketamine), or not yet (buprenorphine) investigated.

Effects of the adjunctive treatment of antidepressants with opiorphin on a panic-like defensive response in rats.

Background: Antidepressants are the first-choice for pharmacological treatment of panic disorder. However, they present disadvantages, such as delayed therapeutic effect, many side effects and a considerable rate of non-responders. These shortcomings prompt the development of new therapeutic strategies.

B2-kinin receptors in the dorsal periaqueductal gray are implicated in the panicolytic-like effect of opiorphin.

Reported results have shown that the pentapeptide opiorphin inhibits oligopeptidases that degrade brain neuropeptides, and has analgesic and antidepressant effects in experimental animals, without either tolerance or dependency after chronic administration. In a previous study we showed that opiorphin has a panicolytic-like effect in the dorsal periaqueductal gray (dPAG) electrical stimulation test (EST), mediated by the μ-opioid receptor (MOR). This study further analyzes the mechanism of opiorphin panicolytic action, using the EST and drug injection inside the dPAG.

What we imagine is what we do? A critical overview about mental imagery as a strategy to study human defensive responses.

There is not a single and perfect instinctive behavior to react to threatening situations. However, the study of particular features of these situations suggests the existence of prototypical emotional reactions and associated defensive behaviors. Since all living beings are subjected to common evolutionary pressures, such as predation and conspecific competition, it is plausible that there is conservation of some basic defensive responses in their behavioral repertoire.

μ-Opioid and 5-HT1A receptors in the dorsomedial hypothalamus interact for the regulation of panic-related defensive responses.

The dorsomedial hypothalamus (DMH) and the dorsal periaqueductal gray (DPAG) have been implicated in the genesis and regulation of panic-related defensive behaviors, such as escape. Previous results point to an interaction between serotonergic and opioidergic systems within the DPAG to inhibit escape, involving µ-opioid and 5-HT1A receptors (5-HT1AR). In the present study we explore this interaction in the DMH, using escape elicited by electrical stimulation of this area as a panic attack index.

Panicolytic-like action of bradykinin in the dorsal periaqueductal gray through μ-opioid and B2-kinin receptors.

A wealth of evidence has shown that opioid and kinin systems may control proximal defense in the dorsal periaqueductal gray matter (dPAG), a critical panic-associated area. Studies with drugs that interfere with serotonin-mediated neurotransmission suggest that the μ-opioid receptor (MOR) synergistically interacts with the 5-HT receptor in the dPAG to inhibit escape, a panic-related behavior. A similar inhibitory effect has also been reported after local administration of bradykinin (BK), which is blocked by the non-selective opioid receptor antagonist naloxone.

Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the κ-opioid receptor antagonist Nor-BNI.

Panic patients may have abnormalities in serotonergic and opioidergic neurotransmission. The dorsal periaqueductal gray (dPAG) plays an important role in organizing proximal defense, related to panic attacks. The 5-HT receptor (5-HT-R) is involved in regulating escape behavior that is organized in the dPAG.

Translational approach to the pathophysiology of panic disorder: Focus on serotonin and endogenous opioids.

Panic patients experience recurrent panic attacks. Two main neurochemical hypotheses have been proposed to explain this vulnerability. The first suggests that panic patients have deficient serotonergic inhibition of neurons localized in the dorsal periaqueductal gray matter of the midbrain that organizes defensive reactions to cope with proximal threats as well as of sympathomotor control areas of the rostral ventrolateral medulla that generate neurovegetative symptoms of the panic attack.

Behavioral and neuroimaging responses induced by mental imagery of threatening scenarios.

Functional neuroimaging studies have shown that actual situations of uncertain or distant threats increase the activity of forebrain regions, whereas proximal threats increase the activity of the dorsal midbrain. This experiment aimed at testing the hypothesis that brain activity elicited by imagined scenarios of threats with two different magnitudes, potential and imminent, resembles that found in response to actual threats. First, we measured subjective responses to imagined scenarios of potential and imminent threats compared with neutral and pleasant scenarios.

Opiorphin causes a panicolytic-like effect in rat panic models mediated by μ-opioid receptors in the dorsal periaqueductal gray.

Reported evidence indicates that endogenous opioid peptides regulate the expression of escape behavior in rats, a panic-related defensive response, through μ-opioid receptors (MORs) in the dorsal periaqueductal gray (dPAG). These peptides are rapidly catabolized by degrading enzymes, including neutral endopeptidase (NEP) and aminopeptidase N (APN). Opiorphin is a peptide inhibitor of both NEP and APN and potentiates the action of endogenous enkephalins.

New Findings on the Neurotransmitter Modulation of Defense in the Dorsal Periaqueductal Gray.

The dorsal periaqueductal gray (DPAG) has long been implicated in the pathophysiology of anxiety, particularly in panic disorder (PD). Evidence obtained with animal models indicates that different neurotransmitters/neuromodulators in this midbrain area are involved in the regulation of anxiety- (e.g.

Pharmacological evidence for the mediation of the panicolytic effect of fluoxetine by dorsal periaqueductal gray matter μ-opioid receptors.

Previously reported results have shown that the inhibitory effect of fluoxetine on escape behavior, interpreted as a panicolytic-like effect, is blocked by pretreatment with either the opioid receptor antagonist naloxone or the 5-HT1A receptor (5-HT1A-R) antagonist WAY100635 via injection into the dorsal periaqueductal gray matter (dPAG). Additionally, reported evidence indicates that the μ-opioid receptor (MOR) interacts with the 5-HT1A-R in the dPAG. In the present work, pretreatment of the dPAG with the selective MOR blocker CTOP antagonized the anti-escape effect of chronic fluoxetine (10 mg/kg, i.

Early life stress in depressive patients: role of glucocorticoid and mineralocorticoid receptors and of hypothalamic-pituitary-adrenal axis activity.

Depression is a chronic, recurrent and long-term disorder characterized by high rates of impairment and several comorbidities. Early life stress (ELS) is associated with the increased risk for developing depression in adulthood, influences its clinical course and predicts a poorer treatment outcome. Stressful life events play an important role in the pathogenesis of depression, being well established as acute triggers of psychiatric illness.

Interaction between μ-opioid and 5-HT1A receptors in the regulation of panic-related defensive responses in the rat dorsal periaqueductal grey.

A wealth of evidence indicates that the activation of 5-HT1A and 5-HT2A receptors in the dorsal periaqueductal grey matter (dPAG) inhibits escape, a panic-related defensive behaviour. Results that were previously obtained with the elevated T-maze test of anxiety/panic suggest that 5-HT1A and μ-opioid receptors in this midbrain area work together to regulate this response. To investigate the generality of this finding, we assessed whether the same cooperative mechanism is engaged when escape is evoked by a different aversive stimulus electrical stimulation of the dPAG.

Experimental public speaking: contributions to the understanding of the serotonergic modulation of fear.

Public speaking is widely used as a model of experimental fear and anxiety. This review aimed to evaluate the effects of pharmacological challenges on public speaking responses and their implications for the understanding of the neurobiology of normal and pathological anxiety, specifically panic disorder. We also describe methodological features of experimental paradigms using public speaking as an inducer of fear and stress.

Executive and modulatory neural circuits of defensive reactions: implications for panic disorder.

The present review covers two independent approaches, a neuroanatomical and a pharmacological (focused on serotonergic transmission), which converge in highlighting the critical role of the hypothalamus and midbrain periaqueductal gray matter in the generation of panic attacks and in the mechanism of action of current antipanic medication. Accordingly, innate and learned fear responses to different threats (i.e.

Serotonin in anxiety and panic: contributions of the elevated T-maze.

The elevated T-maze (ETM) was developed to test the hypothesis that serotonin (5-HT) plays an opposing role in the regulation of defensive behaviors associated with anxiety and panic. This test allows the measurement in the same rat of inhibitory avoidance acquisition, related to generalized anxiety disorder, and of one-way escape, associated with panic disorder. The evidence so far reported with the ETM supports the above hypothesis and indicates that: (1) whereas 5-HT neurons located at the dorsal raphe nucleus are involved in the regulation of both inhibitory avoidance and escape, those of the median raphe nucleus are primarily implicated in the former task; (2) facilitation of 5-HT1A- and 5-HT2A-mediated neurotransmission in the dorsal periaqueductal gray (dPAG) is likely to mediate the panicolytic drug action; (3) stimulation of 5-HT2C receptors in the basolateral amygdala increases anxiety and is implicated in the anxiogenesis caused by short-term administration of antidepressant drugs, and (4) 5-HT1A and the μ-opioid receptors work together in the dPAG to modulate escape or panic attacks.

The median raphe nucleus in anxiety revisited.

Although the role of the median raphe nucleus (MRN) in the regulation of anxiety has received less attention than that of the dorsal raphe nucleus (DRN) there is substantial evidence supporting this function. Reported results with different animal models of anxiety in rats show that whereas inactivation of serotonergic neurons in the MRN causes anxiolysis, the stimulation of the same neurons is anxiogenic. In particular, studies using the elevated T-maze comparing serotonergic interventions in the MRN and in the DRN indicate that the former affect only the inhibitory avoidance task, which has been related to generalized anxiety.

Cooperative regulation of anxiety and panic-related defensive behaviors in the rat periaqueductal grey matter by 5-HT1A and μ-receptors.

Previous results with the elevated T-maze (ETM) test indicate that the antipanic action of serotonin (5-HT) in the dorsal periaqueductal grey (dPAG) depends on the activation endogenous opioid peptides. The aim of the present work was to investigate the interaction between opioid- and serotonin-mediated neurotransmission in the modulation of defensive responses in rats submitted to the ETM. The obtained results showed that intra-dPAG administration of morphine significantly increased escape latency, a panicolytic-like effect that was blocked by pre-treatment with intra-dPAG injection of either naloxone or the 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl] ethyl] -N- 2- pyridinyl-ciclohexanecarboxamide maleate (WAY-100635).

Modeling panic disorder in rodents.

Panic disorder (PD) is a subtype of anxiety disorder in which the core phenomenon is the spontaneous occurrence of panic attacks. Although studies with laboratory animals have been instrumental for the understanding of its neurobiology and treatment, few review articles have focused on the validity of the currently used animal models for studying this psychopathology. Therefore, the aim of the present paper is to discuss the strengths and limits of these models in terms of face, construct and predictive validity.

The 5-HT1D/1B receptor agonist sumatriptan enhances fear of simulated speaking and reduces plasma levels of prolactin.

This study measured the effects of the preferential 5-HT1D/1B receptor agonist sumatriptan in healthy volunteers who performed the Simulated Public Speaking Test (SPST), which recruits the neural network involved in panic disorder and social anxiety disorder. In a double-blind, randomised experiment, 36 males received placebo (12), 50 mg (12) or 100 mg (12) of sumatriptan 2 h before the SPST. Subjective, physiological and hormonal measures were taken before, during and after the test.

The panicolytic-like effect of fluoxetine in the elevated T-maze is mediated by serotonin-induced activation of endogenous opioids in the dorsal periaqueductal grey.

Serotonin (5-HT), opioids and the dorsal periaqueductal grey (DPAG) have been implicated in the pathophysiology of panic disorder. In order to study 5-HT-opioid interaction, the opioid antagonist naloxone was injected either systemically (1 mg/kg, i.p.

Reciprocal modulation of cognitive and emotional aspects in pianistic performances.

Background: High level piano performance requires complex integration of perceptual, motor, cognitive and emotive skills. Observations in psychology and neuroscience studies have suggested reciprocal inhibitory modulation of the cognition by emotion and emotion by cognition. However, it is still unclear how cognitive states may influence the pianistic performance.