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Donald F Klein - One of the best experts on this subject based on the ideXlab platform.
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Lifelong Opioidergic Vulnerability Through Early Life Separation: A Recent Extension of the False Suffocation Alarm Theory of Panic Disorder
Neuroscience & Biobehavioral Reviews, 2014Co-Authors: Maurice Preter, Donald F KleinAbstract:Suffocation-False Alarm Theory (Klein, Arch Gen Psychiatry 50:306–317, 1993) postulates the existence of an evolved physiologic suffocation alarm system that monitors information about potential suffocation. Panic attacks maladaptively occur when the alarm is erroneously triggered. The expanded Suffocation-False Alarm Theory (Preter and Klein, Biol Psychiatry 32(3):603–612, 2008) hypothesizes that endogenous Opioidergic dysregulation may underlie the respiratory pathophysiology and suffocation sensitivity in panic disorder. Opioidergic dysregulation increases sensitivity to CO2, separation distress and panic attacks. That sudden loss, bereavement and childhood separation anxiety are also antecedents of “spontaneous” panic requires an integrative explanation. Our work unveiling the lifelong endogenous opioid system impairing effects of childhood parental loss (CPL) and parental separation in non-ill, normal adults opens a new experimental, investigatory area.
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Lifelong Opioidergic Vulnerability Through Early Life Separation: A Recent Extension of the False Suffocation Alarm Theory of Panic Disorder
Neuroscience & Biobehavioral Reviews, 2014Co-Authors: Maurice Preter, Donald F KleinAbstract:The present paper is the edited version of our presentations at the "First World Symposium On Translational Models Of Panic Disorder", in Vitoria, E.S., Brazil, on November 16-18, 2012. We also review relevant work that appeared after the conference. Suffocation-False Alarm Theory (Klein, 1993) postulates the existence of an evolved physiologic suffocation alarm system that monitors information about potential suffocation. Panic attacks maladaptively occur when the alarm is erroneously triggered. The expanded Suffocation-False Alarm Theory (Preter and Klein, 2008) hypothesizes that endogenous Opioidergic dysregulation may underlie the respiratory pathophysiology and suffocation sensitivity in panic disorder. Opioidergic dysregulation increases sensitivity to CO2, separation distress and panic attacks. That sudden loss, bereavement and childhood separation anxiety are also antecedents of "spontaneous" panic requires an integrative explanation. Our work unveiling the lifelong endogenous opioid system impairing effects of childhood parental loss (CPL) and parental separation in non-ill, normal adults opens a new experimental, investigatory area.
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controlled cross over study in normal subjects of naloxone preceding lactate infusions respiratory and subjective responses relationship to endogenous opioid system suffocation false alarm theory and childhood parental loss
Psychological Medicine, 2011Co-Authors: Maurice Preter, S H Lee, Eva Petkova, Marina Vannucci, Scott Y H Kim, Donald F KleinAbstract:Background The expanded suffocation false alarm theory (SFA) hypothesizes that dysfunction in endogenous Opioidergic regulation increases sensitivity to CO 2 , 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. Method 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. Results Impairment of the endogenous opioid system by naloxone accentuates TV and symptomatic response to lactate. This interaction is substantially lessened by CPL. Conclusions 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.
Maurice Preter - One of the best experts on this subject based on the ideXlab platform.
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Lifelong Opioidergic Vulnerability Through Early Life Separation: A Recent Extension of the False Suffocation Alarm Theory of Panic Disorder
Neuroscience & Biobehavioral Reviews, 2014Co-Authors: Maurice Preter, Donald F KleinAbstract:Suffocation-False Alarm Theory (Klein, Arch Gen Psychiatry 50:306–317, 1993) postulates the existence of an evolved physiologic suffocation alarm system that monitors information about potential suffocation. Panic attacks maladaptively occur when the alarm is erroneously triggered. The expanded Suffocation-False Alarm Theory (Preter and Klein, Biol Psychiatry 32(3):603–612, 2008) hypothesizes that endogenous Opioidergic dysregulation may underlie the respiratory pathophysiology and suffocation sensitivity in panic disorder. Opioidergic dysregulation increases sensitivity to CO2, separation distress and panic attacks. That sudden loss, bereavement and childhood separation anxiety are also antecedents of “spontaneous” panic requires an integrative explanation. Our work unveiling the lifelong endogenous opioid system impairing effects of childhood parental loss (CPL) and parental separation in non-ill, normal adults opens a new experimental, investigatory area.
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Lifelong Opioidergic Vulnerability Through Early Life Separation: A Recent Extension of the False Suffocation Alarm Theory of Panic Disorder
Neuroscience & Biobehavioral Reviews, 2014Co-Authors: Maurice Preter, Donald F KleinAbstract:The present paper is the edited version of our presentations at the "First World Symposium On Translational Models Of Panic Disorder", in Vitoria, E.S., Brazil, on November 16-18, 2012. We also review relevant work that appeared after the conference. Suffocation-False Alarm Theory (Klein, 1993) postulates the existence of an evolved physiologic suffocation alarm system that monitors information about potential suffocation. Panic attacks maladaptively occur when the alarm is erroneously triggered. The expanded Suffocation-False Alarm Theory (Preter and Klein, 2008) hypothesizes that endogenous Opioidergic dysregulation may underlie the respiratory pathophysiology and suffocation sensitivity in panic disorder. Opioidergic dysregulation increases sensitivity to CO2, separation distress and panic attacks. That sudden loss, bereavement and childhood separation anxiety are also antecedents of "spontaneous" panic requires an integrative explanation. Our work unveiling the lifelong endogenous opioid system impairing effects of childhood parental loss (CPL) and parental separation in non-ill, normal adults opens a new experimental, investigatory area.
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controlled cross over study in normal subjects of naloxone preceding lactate infusions respiratory and subjective responses relationship to endogenous opioid system suffocation false alarm theory and childhood parental loss
Psychological Medicine, 2011Co-Authors: Maurice Preter, S H Lee, Eva Petkova, Marina Vannucci, Scott Y H Kim, Donald F KleinAbstract:Background The expanded suffocation false alarm theory (SFA) hypothesizes that dysfunction in endogenous Opioidergic regulation increases sensitivity to CO 2 , 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. Method 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. Results Impairment of the endogenous opioid system by naloxone accentuates TV and symptomatic response to lactate. This interaction is substantially lessened by CPL. Conclusions 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.
Leda Menescaldeoliveira - One of the best experts on this subject based on the ideXlab platform.
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Opioidergic and gabaergic mechanisms in the rostral ventromedial medulla modulate the nociceptive response of vocalization in guinea pigs
Brain Research Bulletin, 2010Co-Authors: Luis F Da Silva, Marcio Ramos Coutinho, Leda MenescaldeoliveiraAbstract:Abstract Vocalization generated by the application of a noxious stimulus is an integrative response related to the affective-motivational component of pain. The rostral ventromedial medulla (RVM) plays an important role in descending pain modulation, and opiates play a major role in modulation of the antinociception mediated by the RVM. Further, it has been suggested that morphine mediates antinociception indirectly, by inhibition of tonically active GABAergic neurons. The current study evaluated the effects of the opioids and GABA agonists and antagonists in the RVM on an affective-motivational pain model. Additionally, we investigated the Opioidergic–GABAergic interaction in the RVM in the vocalization response to noxious stimulation. Microinjection of either morphine (4.4 nmol/0.2 μl) or bicuculline (0.4 nmol/0.2 μl) into the RVM decreased the vocalization index, whereas application of the GABA A receptor agonist, muscimol (0.5 nmol/0.2 μl) increased the vocalization index during noxious stimulation. Furthermore, prior microinjection of either the opioid antagonist naloxone (2.7 nmol/0.2 μl) or muscimol (0.25 nmol/0.2 μl) into the RVM blocked the reduction in vocalization index induced by morphine. These observations suggest an antinociceptive and pro-nociceptive role of the Opioidergic and GABAergic neurotransmitters in the RVM, respectively. Our data show that opioids have an antinociceptive effect in the RVM, while GABAergic neurotransmission is related to the facilitation of nociceptive responses. Additionally, our results indicate that the antinociceptive effect of the opioids in the RVM could be mediated by a disinhibition of tonically active GABAergic interneurons in the downstream projection neurons of the descending pain control system; indicating an interaction between the Opioidergic and GABAergic pathways of pain modulation.
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role of Opioidergic and gabaergic neurotransmission of the nucleus raphe magnus in the modulation of tonic immobility in guinea pigs
Brain Research Bulletin, 2007Co-Authors: Luis Felipe Souza Da Silva, Leda MenescaldeoliveiraAbstract:Abstract Tonic immobility (TI) is an inborn defensive behavior characterized by a temporary state of profound and reversible motor inhibition elicited by some forms of physical restraint. Previous results from our laboratory have demonstrated that nucleus raphe magnus (NRM) is also a structure involved in the modulation of TI behavior, as chemical stimulation through carbachol decreases the duration of TI in guinea pigs. In view of the fact that GABAergic and Opioidergic circuits participate in the regulation of neuronal activity in the NRM and since these neurotransmitters are also involved in the modulation of TI, the objective of the present study was to evaluate the role of these circuits of the NRM in the modulation of the behavioral TI response. Microinjection of morphine (4.4 nmol/0.2 μl) or bicuculline (0.4 nmol/0.2 μl) into the NRM increased the duration of TI episodes while muscimol (0.5 nmol/0.2 μl) decreased it. The effect of morphine injection into the NRM was blocked by previous microinjection of naloxone (2.7 nmol/0.2 μl). Muscimol at 0.25 nmol did not produce any change in TI duration; however, it blocked the increased response induced by morphine. Our results indicate a facilitatory role of Opioidergic neurotransmission in the modulation of the TI response within the NRM, whereas GABAergic activity plays an inhibitory role. In addition, in the present study the modulation of TI in the NRM possibly occurred via an interaction between Opioidergic and GABAergic systems, where the Opioidergic effect might be due to inhibition of tonically active GABAergic interneurons.
Horacio Vanegas - One of the best experts on this subject based on the ideXlab platform.
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antinociception induced by intravenous dipyrone metamizol upon dorsal horn neurons involvement of endogenous opioids at the periaqueductal gray matter the nucleus raphe magnus and the spinal cord in rats
Brain Research, 2005Co-Authors: Enrique Vazquez, Norma Edenia Batista Hernandez, William Escobar, Horacio VanegasAbstract:Microinjection of dipyrone (metamizol) into the periaqueductal gray matter (PAG) in rats causes antinociception. This is mediated by endogenous Opioidergic circuits located in the PAG itself, in the nucleus raphe magnus and adjacent structures, and in the spinal cord. The clinical relevance of these findings, however, is unclear. Therefore, in the present study, dipyrone was administered intravenously, and the involvement of endogenous Opioidergic circuits in the so-induced antinociception was investigated. In rats, responses of dorsal spinal wide-dynamic range neurons to mechanical noxious stimulation of a hindpaw were strongly inhibited by intravenous dipyrone (200 mg/kg). This effect was abolished by microinjection of naloxone (0.5 μg/0.5 μl) into the ventrolateral and lateral PAG or into the nucleus raphe magnus or by direct application of naloxone (50 μg/50 μl) onto the spinal cord surface above the recorded neuron. These results show that dipyrone, a non-opioid analgesic with widespread use in Europe and Latin America, when administered in a clinically relevant fashion causes antinociception by activating endogenous Opioidergic circuits along the descending pain control system.
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The antinociceptive effect of PAG-microinjected dipyrone in rats is mediated by endogenous opioids of the rostral ventromedial medulla
Brain Research, 2000Co-Authors: Enrique Vásquez, Horacio VanegasAbstract:Microinjection of non-opioid analgesics, such as dipyrone (DIP), into the periaqueductal gray matter (PAG) in rats causes an inhibition of nociceptive circuits in the spinal cord. We have herein investigated whether this effect is mediated by Opioidergic mechanisms in the rostral ventromedial medulla (RVM), which is an important relay between the PAG and the spinal cord. The responses of spinal wide-dynamic-range neurons to noxious stimulation of their receptive field (RF) were inhibited by microinjection of DIP (100 μg/0.5 μl) into PAG. Subsequent microinjection of naloxone (NAL; 0.5 μg/0.5 μl) into RVM reversed this inhibition. The present and previous results suggest that non-opioid analgesics, as well as opiates, inhibit nociception by activating descending Opioidergic mechanisms in PAG and RVM.
Till Sprenger - One of the best experts on this subject based on the ideXlab platform.
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Advance Access publication February 21, 2008 The Runner’s High: Opioidergic Mechanisms in the Human Brain
2015Co-Authors: Henning Boecker, Michael Valet, Till Sprenger, Gjermund Henriksen, Mary E. Spilker, Achim Berthele, J. Wagner, R. Tolle, Fe Klinische Funktionelle, Neurobildgebung Rheinische Friedrich-wilhelms-universitätAbstract:The runner’s high describes a euphoric state resulting from long-distance running. The cerebral neurochemical correlates of exercise-induced mood changes have been barely investigated so far. We aimed to unravel the Opioidergic mechanisms of the runner’s high in the human brain and to identify the relationship to perceived euphoria. We performed a positron emission tomography ‘‘ligand activation’ ’ study with the nonselective Opioidergic ligand 6-O-(2-[18F]fluoroethyl)-6-O-desmethyldiprenorphine ([18F]FDPN). Ten athletes were scanned at 2 separate occasions in random order, at rest and after 2 h of endurance running (21.5 6 4.7 km). Binding kinetics of [18F]FDPN were quantified by basis pursuit denoising (DEPICT software). Statistical parametric mapping (SPM2) was used for voxelwise analyses to determine relative changes in ligand binding after running and correlations of opioid binding with euphoria ratings. Reductions in opioid receptor availability were identified preferentially in prefrontal and limbic/paralimbic brain structures. The level of euphoria was significantly increased after running and was inversely correlated with opioid binding in prefrontal/orbitofrontal cortices, the anterior cingulate cortex, bilateral insula, parainsular cortex, and temporoparietal regions. These findings support the ‘‘opioid theory’ ’ of the runner’s high and suggest region-specific effects in frontolimbic brain areas that are involved in the processing of affective states and mood
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Effects of Aerobic Exercise on Mood and Human Opioidergic Activation Measured by Positron Emission Tomography
Functional Neuroimaging in Exercise and Sport Sciences, 2012Co-Authors: Henning Boecker, Thomas R. Tölle, Michael Valet, Till SprengerAbstract:According to the often-cited “endorphin hypothesis”, endogenous Opioidergic transmitter release has been postulated as the neurochemical basis of some of the psychophysical effects associated with endurance exercise, in particular mood changes. This chapter provides an overview on the applicability of positron emission tomography (PET) ligand activation studies with Opioidergic tracers for imaging endogenous Opioidergic transmission associated with exercise.
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The Runner's High: Opioidergic Mechanisms in the Human Brain
Cerebral cortex (New York N.Y. : 1991), 2008Co-Authors: Henning Boecker, Michael Valet, Till Sprenger, Gjermund Henriksen, Mary E. Spilker, Klaus Wagner, Achim Berthele, Marcus Koppenhoefer, Thomas R. TölleAbstract:The runner's high describes a euphoric state resulting from long-distance running. The cerebral neurochemical correlates of exercise-induced mood changes have been barely investigated so far. We aimed to unravel the Opioidergic mechanisms of the runner's high in the human brain and to identify the relationship to perceived euphoria. We performed a positron emission tomography "ligand activation" study with the nonselective Opioidergic ligand 6-O-(2-[(18)F]fluoroethyl)-6-O-desmethyldiprenorphine ([(18)F]FDPN). Ten athletes were scanned at 2 separate occasions in random order, at rest and after 2 h of endurance running (21.5 +/- 4.7 km). Binding kinetics of [(18)F]FDPN were quantified by basis pursuit denoising (DEPICT software). Statistical parametric mapping (SPM2) was used for voxelwise analyses to determine relative changes in ligand binding after running and correlations of opioid binding with euphoria ratings. Reductions in opioid receptor availability were identified preferentially in prefrontal and limbic/paralimbic brain structures. The level of euphoria was significantly increased after running and was inversely correlated with opioid binding in prefrontal/orbitofrontal cortices, the anterior cingulate cortex, bilateral insula, parainsular cortex, and temporoparietal regions. These findings support the "opioid theory" of the runner's high and suggest region-specific effects in frontolimbic brain areas that are involved in the processing of affective states and mood.
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Opioidergic changes in the pineal gland and hypothalamus in cluster headache: A ligand PET study
Neurology, 2006Co-Authors: Till Sprenger, Michael Valet, Mary E. Spilker, Frode Willoch, M. Miederer, F. Schindler, Achim Berthele, Stefanie Förderreuther, Andreas Straube, I. StangierAbstract:Using PET with the Opioidergic ligand [ 11 C]diprenorphine, the authors demonstrate decreased tracer binding in the pineal gland of cluster headache patients vs healthy volunteers. Opioid receptor availability in the hypothalamus and cingulate cortex depended on the duration of the headache disorder. Therefore, the pathophysiology of cluster headache may relate to Opioidergic dysfunction in circuitries generating the biologic clock.
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Opioidergic activation in the medial pain system after heat pain.
Pain, 2006Co-Authors: Till Sprenger, Henning Boecker, Michael Valet, Gjermund Henriksen, Mary E. Spilker, Frode Willoch, Klaus Wagner, Hans Wester, Thomas R. TölleAbstract:Opioids modulate the affective component of pain and in vivo data indicate that opioids induce activation changes in the rostral ACC, insula and other brain areas. Hence, Opioidergic release is to be expected in these brain regions following experimental pain stimulation. We examined healthy volunteers during heat pain and control subjects during rest using [18F]fluorodiprenorphine-PET. Pain stimulation led to significant reduction of diprenorphine binding in limbic and paralimbic brain areas including the rostral ACC and insula. The finding of altered Opioidergic receptor availability in the rostral ACC after experimental nociceptive pain is novel and provides direct evidence for the involvement of this region in endogenous Opioidergic inhibition of pain.