Participation of opioid receptors in the cytoprotective effect of chronic normobaric hypoxia

We studied the role of the delta, micro, and kappa opioid receptor (OR) subtypes in the cardioprotective effect of chronic continuous normobaric hypoxia (CNH) in the model of acuteanoxia-reoxygenation of isolated cardiomyocytes. Adaptation of rats to CNH was performed by their exposure to atmosphere containing 12% of O(2) for 21 days. Anoxia-reoxygenation of cardiomyocytes isolated from normoxiccontrol rats caused the death of 51 % of cells and lactate dehydrogenase (LDH) release. Adaptation of rats to CNH resulted in the anoxia/reoxygenation-induced cardiomyocyte death of only 38 %, and reduced the LDH release by 25 %. Pre-incubation of the cells with either the non-selective OR (opioid receptor) blocker naloxone (300 nM/l), the delta OR antagonist TIPP(psi) (30 nM/l), the selective delta(2) OR antagonist naltriben (1 nM/l) or the micro OR antagonist CTAP (100 nM/l) for 25 minutes before anoxia abolished the reduction of cell death and LDH release afforded by CNH. The antagonist of delta(1) OR BNTX (1 nM/l) or the kappa OR antagonist nor-binaltorphimine (3 nM/l) did not influence the cytoprotective effects of CNH. Taken together, the cytoprotective effect of CNH is associated with the activation of the delta(2) and micro OR localized on cardiomyocytes.

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The Role of Dynorphin and the Kappa Opioid Receptor in Schizophrenia and Major Depressive Disorder: A Translational Approach

10.1007/164_2020_396 ◽

2020 ◽

Author(s):

Samuel David Clark

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Healthy Volunteers ◽

Opioid Receptor ◽

Clinical Data ◽

Potential Role ◽

Kappa Opioid Receptor ◽

Kappa Opioid ◽

Major Depressive

AbstractThe kappa opioid receptor (KOR) and its endogenous ligands dynorphins (DYN) have been implicated in the development or symptomatology of a variety of neuropsychiatric disorders. This review covers a brief history of the development of KOR agonists and antagonists, their effects in healthy volunteers, and the potential role of DYN/KOR dysfunction in schizophrenia and major depressive disorder from a translational perspective. The potential role of DYN/KOR dysfunction in schizophrenia is based on several lines of evidence. Selective KOR agonists induce affective states in healthy volunteers with similarities to the symptoms of schizophrenia. Studies have shown increased DYN in patients with schizophrenia, although the data have been mixed. Finally, meta-analytic data have shown that opioid antagonists are associated with reductions in the symptoms of schizophrenia. The potential role of DYN/KOR dysfunction in major depressive disorder is also based on a combination of preclinical and clinical data. Selective KOR agonists have shown pro-depressive effects in human volunteers, while selective KOR antagonists have shown robust efficacy in several preclinical models of antidepressant activity. Small studies have shown that nonselective KOR antagonists may have efficacy in treatment-resistant depression. Additionally, recent clinical data have shown that the KOR may be an effective target for treating anhedonia, a finding relevant to both schizophrenia and depression. Finally, recommendations are provided for translating preclinical models for schizophrenia and major depressive disorder into the clinic.

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Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus

Neuropharmacology ◽

10.1016/j.neuropharm.2015.08.027 ◽

2015 ◽

Vol 99 ◽

pp. 600-609 ◽

Cited By ~ 16

Author(s):

Jenny Morgenweck ◽

Kevin J. Frankowski ◽

Thomas E. Prisinzano ◽

Jeffrey Aubé ◽

Laura M. Bohn

Keyword(s):

Mouse Model ◽

Opioid Receptor ◽

Kappa Opioid Receptor ◽

Kappa Opioid ◽

Receptor Modulation

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pHe, [Ca2+]e, and cell death during metabolic inhibition: role of phospholipase A2 and sarcolemmal phospholipids

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.274.1.h18 ◽

1998 ◽

Vol 274 (1) ◽

pp. H18-H26 ◽

Cited By ~ 1

Author(s):

Jan A. Post ◽

Sheng-Yong Wang ◽

Glenn A. Langer

Keyword(s):

Cell Death ◽

Arachidonic Acid ◽

Lactate Dehydrogenase ◽

Present Model ◽

Cell Lysis ◽

Metabolic Inhibition ◽

Ldh Release ◽

External Ph ◽

Sarcolemmal Integrity

This study measures cellular lactate dehydrogenase (LDH) release during metabolic inhibition as a monitor of sarcolemmal integrity as affected by variation of external pH (pHe) and Ca2+ concentration ([Ca2+]e). The sigmoidal relationship between pHe and LDH release and pHe and net Ca2+ uptake was essentially identical with the 50% maximal value occurring at pH 7.0 for both. This suggests that a process(es) sensitive to both pHe and [Ca2+]eplays a role in cell lysis during the course of metabolic inhibition. Variation of pHe during metabolic inhibition did not alter the decline in cellular ATP, nor did it affect changes in sarcolemmal phospholipid topology. Intracellular pH followed changes of pHe with a few minutes lag. Cell lysis increased in a graded manner as pHe and [Ca2+]ewere increased, but pHe was the sole determinant of lysis, i.e., [Ca2+]elevel had no effect, at the lowest (6.2) and the highest (8.0) pHe levels. pHe variation did not affect the release of radiolabeled arachidonic acid, nor did inhibitors of phospholipase A2(PLA2) affect cell lysis at varying pHe. Therefore, cellular PLA2 activation could not be implicated for a role in cell lysis in the present model of metabolic inhibition. Alternatively, we propose that Ca2+ binding to the cytoplasmic leaflet, in combination with membrane alterations secondary to the metabolic insult, combine to destabilize the sarcolemma (20). This Ca2+ binding to the negatively charged phosphatidylserine results in the expression of the bilayer destabilizing effect of phosphatidylethanolamine. This Ca2+ binding is greatly diminished by lowered pH, resulting in an attenuation of cell lysis.

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