naloxone and Panic-Disorder

To review the mechanisms for the perception of dyspnea and to consider the plausibility of interventions that palliate dyspnea after optimal treatment of the underlying disease.. Activation of sensory receptors by blood gas abnormalities, mechanical respiratory loads, and hyperinflation provides afferent information to the central nervous system for integration and processing. It has been proposed that a discriminative pathway processes afferent impulses to the somatosensory cortex that reflects the intensity of dyspnea, whereas an affective pathway projects afferent impulses to structures of the limbic system that reflects the unpleasantness of dyspnea. In one study, patients with chronic obstructive pulmonary disease reported consistently higher ratings of breathlessness after administration of naloxone, an opioid receptor antagonist, compared with physiological saline during high-intensity treadmill exercise. This finding supports the role of endogenous opioids in modulating dyspnea. Nebulized furosemide, anti-inflammatory therapy, and chest wall vibration are potential approaches for modulating lung and chest wall receptors to relieve dyspnea.. Targets for palliating dyspnea in patients with advanced disease include sensory receptors within the lung/chest wall and the central nervous system. The opioid system plays an important role in palliating dyspnea. Both endogenous (β-endorphins) and exogenous (morphine) opioids modulate breathlessness.

Topics: Afferent Pathways; Central Nervous System; Dyspnea; Efferent Pathways; Endorphins; Humans; Naloxone; Narcotic Antagonists; Neurotransmitter Agents; Palliative Care; Panic Disorder; Pulmonary Disease, Chronic Obstructive; Sensory Receptor Cells

The expanded suffocation false alarm theory (SFA) hypothesizes that dysfunction in endogenous opioidergic regulation increases sensitivity to CO2, separation distress and panic attacks. In panic disorder (PD) patients, both spontaneous clinical panics and lactate-induced panics markedly increase tidal volume (TV), whereas normals have a lesser effect, possibly due to their intact endogenous opioid system. We hypothesized that impairing the opioidergic system by naloxone could make normal controls parallel PD patients' response when lactate challenged. Whether actual separations and losses during childhood (childhood parental loss, CPL) affected naloxone-induced respiratory contrasts was explored. Subjective panic-like symptoms were analyzed although pilot work indicated that the subjective aspect of anxious panic was not well modeled by this specific protocol.. Randomized cross-over sequences of intravenous naloxone (2 mg/kg) followed by lactate (10 mg/kg), or saline followed by lactate, were given to 25 volunteers. Respiratory physiology was objectively recorded by the LifeShirt. Subjective symptomatology was also recorded.. Impairment of the endogenous opioid system by naloxone accentuates TV and symptomatic response to lactate. This interaction is substantially lessened by CPL.. Opioidergic dysregulation may underlie respiratory pathophysiology and suffocation sensitivity in PD. Comparing specific anti-panic medications with ineffective anti-panic agents (e.g. propranolol) can test the specificity of the naloxone+lactate model. A screen for putative anti-panic agents and a new pharmacotherapeutic approach are suggested. Heuristically, the experimental unveiling of the endogenous opioid system impairing effects of CPL and separation in normal adults opens a new experimental, investigatory area.

Topics: Adolescent; Adult; Anxiety, Separation; Cross-Over Studies; Female; Humans; Lactic Acid; Male; Middle Aged; Naloxone; Opioid Peptides; Panic Disorder; Respiratory Physiological Phenomena

The lateral hypothalamus (LH) sends neural pathways to structures involved on predator‑related defensive behaviours, escape and antinociception. The aim of this study was to investigate the role played by μ-opioid receptors located on LH neurons in defensive behaviour and unconditioned fear‑induced antinociception elicited by electric stimulation of LH. To achieve the goals, the μ1-opioid receptor selective antagonist naloxonazine was administered at different concentrations in the LH, and the defensive behaviour and fear‑induced antinociception elicited by electrical stimulation of LH were evaluated. The electrical stimulation of LH caused escape behaviour followed by defensive antinociception. Microinjections of naloxonazine in a concentration of 5.0 μg/0.2 μL in the LH decreased the aversive stimulus‑induced escape behaviour thresholds, but diminished defensive antinociception. These findings suggest that μ-opioid receptors of LH can be critical to panic attack‑related symptoms and facilitate the unconditioned fear‑induced antinociception produced by LH neurons activation.

Topics: Animals; Behavior, Animal; Bicuculline; Fear; Hypothalamic Area, Lateral; Naloxone; Narcotic Antagonists; Nociception; Panic; Panic Disorder; Rats; Rats, Wistar; Receptors, Opioid, mu

There is a controversy regarding the key role played by opioid peptide neurotransmission in the modulation of panic-attack-related responses.. Using a prey versus rattlesnakes paradigm, the present work investigated the involvement of the endogenous opioid peptide-mediated system of the inferior colliculus in the modulation of panic attack-related responses.. Wistar rats were pretreated with intracollicular administration of either physiological saline or naloxone at different concentrations and confronted with rattlesnakes ( Crotalus durissus terrificus). The prey versus rattlesnake confrontations were performed in a polygonal arena for snakes. The defensive behaviors displayed by prey (defensive attention, defensive immobility, escape response, flat back approach and startle) were recorded twice: firstly, over a period of 15 min the presence of the predator and a re-exposure was performed 24 h after the confrontation, when animals were exposed to the experimental enclosure without the rattlesnake.. The intramesencephalic non-specific blockade of opioid receptors with microinjections of naloxone at higher doses decreased both anxiety- (defensive attention and flat back approach) and panic attack-like (defensive immobility and escape) behaviors, evoked in the presence of rattlesnakes and increased non-defensive responses. During the exposure to the experimental context, there was a decrease in duration of defensive attention.. These findings suggest a panicolytic-like effect of endogenous opioid receptors antagonism in the inferior colliculus on innate (panic attack) and conditioned (anticipatory anxiety) fear in rats threatened by rattlesnakes.

Topics: Animals; Avoidance Learning; Crotalus; Defense Mechanisms; Escape Reaction; Fear; Inferior Colliculi; Male; Naloxone; Opioid Peptides; Panic Disorder; Rats; Rats, Wistar

The endogenous opioid peptide system has been implicated in the neural modulation of fear and anxiety organised by the dorsal midbrain. Furthermore, previous results indicate a fundamental role played by inferior colliculus (IC) opioid mechanisms during the expression of defensive behaviours, but the involvement of the IC µ. The blockade of µ. Taken together, these results suggest that a decrease in µ

Topics: Animals; Anxiety; Behavior, Animal; Crotalus; Disease Models, Animal; Fear; Food Chain; Inferior Colliculi; Naloxone; Narcotic Antagonists; Panic Disorder; Rats; Rats, Wistar; Receptors, Opioid, mu; Signal Transduction

The effects of endogenous opioid peptide antagonists on panic-related responses are controversial. Using elevated mazes and a prey-versus-predator paradigm, we investigated the involvement of the endogenous opioid peptide-mediated system in the modulation of anxiety- and panic attack-induced responses and innate fear-induced antinociception in the present work. Wistar rats were intraperitoneally pretreated with either physiological saline or naloxone at different doses and were subjected to either the elevated plus- or T-maze test or confronted by Crotalus durissus terrificus. The defensive behaviors of the rats were recorded in the presence of the predator and at 24h after the confrontation, when the animals were placed in the experimental enclosure without the rattlesnake. The peripheral non-specific blockade of opioid receptors had a clear anxiolytic-like effect on the rats subjected to the elevated plus-maze but not on those subjected to the elevated T-maze; however, a clear panicolytic-like effect was observed, i.e., the defensive behaviors decreased, and the prey-versus-predator interaction responses evoked by the presence of the rattlesnakes increased. A similar effect was noted when the rats were exposed to the experimental context in the absence of the venomous snake. After completing all tests, the naloxone-treated groups exhibited less anxiety/fear-induced antinociception than the control group, as measured by the tail-flick test. These findings demonstrate the anxiolytic and panicolytic-like effects of opioid receptor blockade. In addition, the fearlessness behavior displayed by preys treated with naloxone at higher doses enhanced the defensive behavioral responses of venomous snakes.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Anxiety Disorders; Attention; Avoidance Learning; Dose-Response Relationship, Drug; Escape Reaction; Fear; Immobility Response, Tonic; Male; Maze Learning; Naloxone; Narcotic Antagonists; Panic Disorder; Predatory Behavior; Rats; Rats, Wistar; Synaptic Transmission

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. The obtained results show that intra-DMH administration of the non-selective opioid receptor antagonist naloxone (0.5 nmol) prevented the panicolytic-like effect of a local injection of serotonin (20 nmol). Pretreatment with the selective μ-opioid receptor (MOR) antagonist CTOP (1 nmol) blocked the panicolytic-like effect of the 5-HT1AR agonist 8-OHDPAT (8 nmol). Intra-DMH injection of the selective MOR agonist DAMGO (0.3 nmol) also inhibited escape behavior, and a previous injection of the 5-HT1AR antagonist WAY-100635 (0.37 nmol) counteracted this panicolytic-like effect. These results offer the first evidence that serotonergic and opioidergic systems work together within the DMH to inhibit panic-like behavior through an interaction between µ-opioid and 5-HT1A receptors, as previously described in the DPAG.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Analgesics, Opioid; Animals; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Escape Reaction; Hypothalamus; Male; Naloxone; Panic; Panic Disorder; Periaqueductal Gray; Piperazines; Pyridines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptors, Opioid, mu; Serotonin; Somatostatin

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). In addition, previous administration of naloxone antagonized both the anti-escape and the anti-avoidance (anxiolytic-like) effect of the 5-HT1A agonist (±)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), but did not affect the anti-escape effect of the 5-HT2A agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). Moreover, the combination of sub-effective doses of locally administered 5-HT and morphine significantly impaired ETM escape performance. Finally, the µ-antagonist D-PHE-CYS-TYR-D-TRP-ORN-THR-PEN (CTOP) blocked the anti-avoidance as well as the anti-escape effect of 8-OHDPAT, and the association of sub-effective doses of the µ-opioid receptor agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin acetate salt (DAMGO) and of 8-OHDPAT had anti-escape and anti-avoidance effects in the ETM. These results suggest a synergic interaction between the 5-HT1A and the µ-opioid receptor at post-synaptic level on neurons of the dPAG that regulate proximal defense, theoretically related to panic attacks.

Topics: Animals; Anxiety; Behavior, Animal; Male; Maze Learning; Morphine; Naloxone; Neurons; Panic; Panic Disorder; Periaqueductal Gray; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptors, Opioid, mu; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

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.) or intra-DPAG (0.2 μg/0.5 μL) to assess its interference with the effect of chronic fluoxetine (10 mg/kg, i.p., daily for 21 days) or of intra-DPAG 5-HT (8 μg/0.5 μL). Drug effects were measured in the one-escape task of the rat elevated T-maze, an animal model of panic. Pretreatment with systemic naloxone antagonized the lengthening of escape latency caused by chronic fluoxetine, considered a panicolytic-like effect that parallels the drug's therapeutic response in the clinics. Pretreatment with naloxone injected intra-DPAG antagonized both the panicolytic effect of chronic fluoxetine as well as that of 5-HT injected intra-DPAG. Neither the performance of the inhibitory avoidance task in the elevated T-maze, a model of generalized anxiety nor locomotion measured in a circular arena was affected by the above drug treatments. These results indicate that the panicolytic effect of fluoxetine is mediated by endogenous opioids that are activated by 5-HT in the DPAG. They also allow reconciliation between the serotonergic and opioidergic hypotheses of panic disorder pathophysiology.

Topics: Animals; Antidepressive Agents, Second-Generation; Fluoxetine; Male; Maze Learning; Motor Activity; Naloxone; Opioid Peptides; Panic Disorder; Periaqueductal Gray; Rats; Rats, Wistar; Serotonin

This study investigates whether naloxone, an opioid receptor antagonist, could render normal controls, normally nonresponsive to panic inducing stimuli, sensitive to the physiological and behavioral effects of sodium lactate, a robust panicogen in panic disorder patients. Twelve normal controls received intravenous naloxone followed by sodium lactate. Four of these subjects underwent a separate infusion with naloxone followed by saline. Respiratory physiological symptoms were measured throughout. Clinical symptoms, assessed by the Acute Panic Inventory (API), an Anxiety Scale, and the Borg Breathlessness Scale, were recorded. Eight of the twelve subjects experienced strong physiological reactivity to naloxone-lactate manifested by significantly increased tidal volume. Concomitant increases in the API and Borg scales were demonstrated; however, fear or anxiety was not affected. The four subjects retested with naloxone followed by saline did not experience significant increases on any measure. These results provide preliminary evidence that endogenous opioid system function may be a key modulator of responsivity to sodium lactate. Dysregulation of the opioid system may potentially underlie critical aspects of panic disorder neurobiology, including respiratory abnormalities and suffocation sensitivity.

Topics: Acute Disease; Adult; Female; Humans; Injections, Intravenous; Lactic Acid; Male; Middle Aged; Naloxone; Narcotic Antagonists; Panic Disorder; Severity of Illness Index; Sodium Chloride