scholarly journals Effects of a κ-Receptor Agonist U-50488 on Bulbar Respiratory Neurons and Its Antagonistic Action Against the μ Receptor-Induced Respiratory Depression in Decerebrate Cats

2001 ◽  
Vol 87 (4) ◽  
pp. 333-337 ◽  
Author(s):  
Akira Haji ◽  
Ryuji Takeda
Keyword(s):  
Respiratory Depression ◽  
Receptor Agonist ◽  
Respiratory Neurons ◽  
Antagonistic Action ◽  
Decerebrate Cats ◽  
Κ Receptor ◽  
Μ Receptor

scholarly journals Novel Molecular Targets of Dezocine and Their Clinical Implications

2014 ◽  
Vol 120 (3) ◽  
pp. 714-723 ◽  
Author(s):  
Renyu Liu ◽  
Xi-Ping Huang ◽  
Alexei Yeliseev ◽  
Jin Xi ◽  
Bryan L. Roth
Keyword(s):  
Opioid Receptor ◽  
Serotonin Transporter ◽  
Receptor Agonist ◽  
Molecular Targets ◽  
Norepinephrine Transporter ◽  
Clinical Implications ◽  
Protein Activation ◽  
G Protein Activation ◽  
Κ Receptor ◽  
Μ Receptor

Abstract Background: Although dezocine is a partial μ-opioid receptor agonist, it is not a controlled substance. Thus, the characterization of the molecular targets of dezocine is critical for scientific and clinical implications. The goal of this study is to characterize molecular targets for dezocine and determine their implications. Methods: A binding screen for dezocine was performed on 44 available receptors and transporter proteins. Functional assays for the novel targets were performed along with computation calculations to locate the binding site. A G protein activation study was performed for the human κ opioid receptor to determine whether dezocine is a κ-antagonist. Data are presented as mean ± standard error. Results: The affinities for dezocine were 3.7 ± 0.7 nM for the μ receptor, 527 ± 70 nM for the δ-receptor, and 31.9 ± 1.9 nM for the κ-receptor. Dezocine failed to induce G protein activation with κ-opioid receptor and concentration dependently inhibited κ-agonist (salvinorin A and nalbuphine)–induced receptor activation, indicating that dezocine is a κ-antagonist. Two novel molecular targets (norepinephrine transporter and serotonin transporter) were identified. Dezocine concentration-dependently inhibited norepinephrine and serotonin reuptake in vitro. The half maximal inhibitory concentrations (expressed as pIC50) were 5.68 ± 0.11 for norepinephrine transporter and 5.86 ± 0.17 for serotonin transporter. Dezocine occupied the binding site for known norepinephrine transporter and serotonin transporter inhibitors. Conclusions: The unique molecular pharmacological profile of dezocine as a partial μ-receptor agonist, a κ-receptor antagonist, and a norepinephrine and serotonin reuptake inhibitor (via norepinephrine transporter and serotonin transporter) was revealed. These discoveries reveal potentially important novel clinical implications and drug interactions of dezocine.

The 5-hydroxytryptamine 4 receptor agonist mosapride does not antagonize morphine-induced respiratory depression

2005 ◽  
Vol 78 (3) ◽  
pp. 278-287 ◽  
Author(s):  
J LOTSCH ◽  
C SKARKE ◽  
A SCHNEIDER ◽  
T HUMMEL ◽  
G GEISSLINGER
Keyword(s):  
Respiratory Depression ◽  
Receptor Agonist

scholarly journals Benefit and Risk Evaluation of Biased μ-Receptor Agonist Oliceridine versus Morphine

2020 ◽  
Vol 133 (3) ◽  
pp. 559-568 ◽  
Author(s):  
Albert Dahan ◽  
C. Jan van Dam ◽  
Marieke Niesters ◽  
Monique van Velzen ◽  
Michael J. Fossler ◽  
...  
Keyword(s):  
Utility Function ◽  
Respiratory Depression ◽  
Receptor Agonist ◽  
Ventilatory Response ◽  
Cold Pressor Test ◽  
Cold Pressor ◽  
Population Pharmacokinetic ◽  
Potency Ratio ◽  
Analgesic Effects ◽  
Hypercapnic Ventilatory Response

Background To improve understanding of the respiratory behavior of oliceridine, a μ-opioid receptor agonist that selectively engages the G-protein–coupled signaling pathway with reduced activation of the β-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility. Methods Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers (n = 30) were reanalyzed. A population pharmacokinetic–pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia ≥ 0.5) – P(respiratory depression ≥ 0.25), where analgesia ≥ 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression ≥ 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median ± standard error of the estimate. Results The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 ± 4.9 ng/ml; morphine 34.3 ± 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 ± 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 ± 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P < 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia. Conclusions These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Acidosis antagonizes intracellular calcium response to κ-opioid receptor stimulation in the rat heart

1999 ◽  
Vol 277 (3) ◽  
pp. C492-C500 ◽  
Author(s):  
Jian-Ming Pei ◽  
Xiao-Chun Yu ◽  
Jin-Song Bian ◽  
Tak-Ming Wong
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
Ventricular Myocytes ◽  
High Concentration ◽  
Receptor Stimulation ◽  
Antagonistic Action ◽  
Extracellular Acidosis ◽  
Opioid Receptor Agonist ◽  
Intracellular Ca ◽  
First Time

To study the effects of κ-opioid receptor stimulation on intracellular Ca2+ concentration ([Ca2+]i) homeostasis during extracellular acidosis, we determined the effects of κ-opioid receptor stimulation on [Ca2+]iresponses during extracellular acidosis in isolated single rat ventricular myocytes, by a spectrofluorometric method. U-50488H (10–30 μM), a selective κ-opioid receptor agonist, dose dependently decreased the electrically induced [Ca2+]itransient, which results from the influx of Ca2+ and the subsequent mobilization of Ca2+ from the sarcoplasmic reticulum (SR). U-50488H (30 μM) also increased the resting [Ca2+]iand inhibited the [Ca2+]itransient induced by caffeine, which mobilizes Ca2+ from the SR, indicating that the effects of the κ-opioid receptor agonist involved mobilization of Ca2+ from its intracellular pool into the cytoplasm. The Ca2+responses to 30 μM U-50488H were abolished by 5 μM nor-binaltorphimine, a selective κ-opioid receptor antagonist, indicating that the event was mediated by the κ-opioid receptor. The effects of the agonist on [Ca2+]iand the electrically induced [Ca2+]itransient were significantly attenuated when the extracellular pH (pHe) was lowered to 6.8, which itself reduced intracellular pH (pHi) and increased [Ca2+]i. The inhibitory effects of U-50488H were restored during extracellular acidosis in the presence of 10 μM ethylisopropyl amiloride, a potent Na+/H+exchange blocker, or 0.2 mM Ni2+, a putative Na+/Ca2+exchange blocker. The observations indicate that acidosis may antagonize the effects of κ-opioid receptor stimulation via Na+/H+and Na+/Ca2+exchanges. When glucose at 50 mM, known to activate the Na+/H+exchange, was added, both the resting [Ca2+]iand pHi increased. Interestingly, the effects of U-50488H on [Ca2+]iand the electrically induced [Ca2+]itransient during superfusion with glucose were significantly attenuated; this mimicked the responses during extracellular acidosis. When a high-Ca2+ (3 mM) solution was superfused, the resting [Ca2+]iincreased; the increase was abolished by 0.2 mM Ni2+, but the pHi remained unchanged. Like the responses to superfusion with high-concentration glucose and extracellular acidosis, the responses of the [Ca2+]iand electrically induced [Ca2+]itransients to 30 μM U-50488H were also significantly attenuated. Results from the present study demonstrated for the first time that extracellular acidosis antagonizes the effects of κ-opioid receptor stimulation on the mobilization of Ca2+ from SR. Activation of both Na+/H+and Na+/Ca2+exchanges, leading to an elevation of [Ca2+]i, may be responsible for the antagonistic action of extracellular acidosis against κ-opioid receptor stimulation.

scholarly journals Analgesic Effect Comparison Between Nalbuphine and Sufentanil for Patient-Controlled Intravenous Analgesia After Cesarean Section

2020 ◽  
Vol 11 ◽  
Author(s):  
Shen Sun ◽  
Yundong Guo ◽  
Tingting Wang ◽  
Shaoqiang Huang
Keyword(s):  
Adverse Events ◽  
Cesarean Section ◽  
Analgesic Effect ◽  
Receptor Agonist ◽  
Cesarean Sections ◽  
Pain Scores ◽  
Intravenous Analgesia ◽  
Degree Of Satisfaction ◽  
Elective Cesarean ◽  
Κ Receptor

Background: Efficient maternal pain relief after cesarean delivery remains challenging, but it is important to improve outcomes for the mother and the newborn during the puerperium. We compared the analgesic effect of nalbuphine (a κ receptor agonist/μ receptor antagonistic) with that of sufentanil (a µ-receptor agonist) in patient-controlled intravenous analgesia (PCIA) after cesarean section.Methods: We enrolled 84 patients scheduled for elective cesarean sections with spinal anesthesia and randomized them into either nalbuphine or sufentanil groups (42 patients each). Pain scores, PCIA drug consumptions, degree of satisfaction, and adverse events were recorded as outcome measures.Results: The pain scores at rest and uterine cramping pain scores in the nalbuphine group were lower than those in the sufentanil group at 6, 12, and 24 h after the operation. Also, the pain scores while switching to a seated position were lower in the nalbuphine group than in the sufentanil group at 6 and 12 h after the operation (p < 0.05). We found no significant differences in the PCIA drug consumption between the two groups. The degree of satisfaction in patients in the nalbuphine group was higher than that of patients in the sufentanil group (p = 0.01). Adverse events did not differ in the two groups.Conclusion: PCIA with nalbuphine provides better analgesia and higher patient satisfaction than sufentanil after cesarean section.

Midbrain and medullary control of postinspiratory activity of the crural and costal diaphragm in vivo

2011 ◽  
Vol 105 (6) ◽  
pp. 2852-2862 ◽  
Author(s):  
Hari H. Subramanian ◽  
Gert Holstege
Keyword(s):  
Inhibitory Effect ◽  
Respiratory Neurons ◽  
Abdominal Muscles ◽  
Anesthetized Rats ◽  
Diaphragm Function ◽  
Three Phase ◽  
Crural Diaphragm ◽  
Decerebrate Cats ◽  
Stimulation Of

Studies on brain stem respiratory neurons suggest that eupnea consists of three phases: inspiration, postinspiration, and expiration. However, it is not well understood how postinspiration is organized in the diaphragm, i.e., whether postinspiration differs in the crural and costal segments of the diaphragm and what the influence is of postinspiratory neurons on diaphragm function during eupnea. In this in vivo study we investigated the postinspiratory activity of the two diaphragm segments during eupnea and the changes in diaphragm function following modulation of eupnea. Postinspiratory neurons in the medulla were stereotaxically localized extracellularly and neurochemically stimulated. We used three types of preparations: precollicularly decerebrated unanesthetized cats and rats and anesthetized rats. In all preparations, during eupnea, postinspiratory activity was found in the crural but not in the costal diaphragm. When eupnea was discontinued in decerebrate cats in which stimulation in the nucleus retroambiguus induced activation of laryngeal or abdominal muscles, all postinspiratory activity in the crural diaphragm was abolished. In decerebrate rats, stimulation of the midbrain periaqueductal gray abolished postinspiration in the crural diaphragm but induced activation in the costal diaphragm. In anesthetized rats, stimulation of medullary postinspiratory neurons abolished the postinspiratory activity of the crural diaphragm. Vagal nerve stimulation in these rats increased the intensity of postinspiratory neuronal discharge in the solitary nucleus, leading to decreased activity of the crural diaphragm. These data demonstrate that three-phase breathing in the crural diaphragm during eupnea exists in vivo and that postinspiratory neurons have an inhibitory effect on crural diaphragm function.

CO2 sensitivity of cat phrenic neurogram during hypoxic respiratory depression

1988 ◽  
Vol 65 (2) ◽  
pp. 736-743 ◽  
Author(s):  
J. E. Melton ◽  
J. A. Neubauer ◽  
N. H. Edelman
Keyword(s):  
Blood Pressure ◽  
Metabolic Acidosis ◽  
Lactic Acidosis ◽  
Respiratory Depression ◽  
Separate Group ◽  
Respiratory Neurons ◽  
Co2 Response ◽  
Co2 Sensitivity ◽  
Lactate Formation ◽  
End Tidal

The CO2 response of the phrenic neurogram before and during CO-induced isocapnic brain hypoxia was studied in peripherally chemodenervated, vagotomized, paralyzed, ventilated cats with blood pressure held constant. During inhalation of 0.5% CO in 40% O2, arterial O2 content (CaO2) was reduced to 40% and minute phrenic activity to 38.4 +/- 9.4% (SE; n = 9) of prehypoxic levels, primarily due to depression of peak phrenic amplitude (PP). CO2 response, defined as the slope of the plot of PP vs. end-tidal PCO2 during CO2 rebreathing, was unaffected by phrenic depression even to the point of total suppression of phrenic activity in two cats. The effect of the tissue metabolic acidosis associated with hypoxia on phrenic CO2 sensitivity was assessed in a separate group of cats by blocking lactate formation during hypoxia with dichloroacetate (DCA). Preventing lactic acidosis during hypoxia did not affect the CO2 response of the phrenic activity during hypoxia. We conclude that 1) hypoxic depression does not limit the ability of central respiratory neurons to respond to CO2, and 2) the failure of DCA to affect the CO2 response of the phrenic neurogram suggests that brain intracellular lactic acidosis does not modify the phrenic response to hypercapnia.

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