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

5-HT1A Receptor Agonist Befiradol Reduces Fentanyl-induced Respiratory Depression, Analgesia, and Sedation in Rats

2015 ◽  
Vol 122 (2) ◽  
pp. 424-434 ◽  
Author(s):  
Jun Ren ◽  
Xiuqing Ding ◽  
John J. Greer
Keyword(s):  
Respiratory Depression ◽  
Receptor Agonist ◽  
Minute Ventilation ◽  
Pharmacological Therapy ◽  
Behavioral Syndrome ◽  
Adult Rats ◽  
Righting Reflex ◽  
And Behavior ◽  
Neural Discharge

Abstract Background: There is an unmet clinical need to develop a pharmacological therapy to counter opioid-induced respiratory depression without interfering with analgesia or behavior. Several studies have demonstrated that 5-HT1A receptor agonists alleviate opioid-induced respiratory depression in rodent models. However, there are conflicting reports regarding their effects on analgesia due in part to varied agonist receptor selectivity and presence of anesthesia. Therefore the authors performed a study in rats with befiradol (F13640 and NLX-112), a highly selective 5-HT1A receptor agonist without anesthesia. Methods: Respiratory neural discharge was measured using in vitro preparations. Plethysmographic recording, nociception testing, and righting reflex were used to examine respiratory ventilation, analgesia, and sedation, respectively. Results: Befiradol (0.2 mg/kg, n = 6) reduced fentanyl-induced respiratory depression (53.7 ± 5.7% of control minute ventilation 4 min after befiradol vs. saline 18.7 ± 2.2% of control, n = 9; P < 0.001), duration of analgesia (90.4 ± 11.6 min vs. saline 130.5 ± 7.8 min; P = 0.011), duration of sedation (39.8 ± 4 min vs. saline 58 ± 4.4 min; P = 0.013); and induced baseline hyperventilation, hyperalgesia, and “behavioral syndrome” in nonsedated rats. Further, the befiradol-induced alleviation of opioid-induced respiratory depression involves sites or mechanisms not functioning in vitro brainstem–spinal cord and medullary slice preparations. Conclusions: The reversal of opioid-induced respiratory depression and sedation by befiradol in adult rats was robust, whereas involved mechanisms are unclear. However, there were adverse concomitant decreases in fentanyl-induced analgesia and altered baseline ventilation, nociception, and behavior.

Fetal cardiovascular and breathing responses to an adenosine A2a receptor agonist in sheep

1998 ◽  
Vol 274 (1) ◽  
pp. R152-R159 ◽  
Author(s):  
Brian J. Koos ◽  
Andrew Chau
Keyword(s):  
Heart Rate ◽  
Respiratory Depression ◽  
Receptor Agonist ◽  
Cgs 21680 ◽  
Carotid Bodies ◽  
A2a Receptor ◽  
Fetal Breathing ◽  
Peripheral Arterial ◽  
Adenosine A2a ◽  
Maximum Rise

CGS-21680 (CGS), a highly selective adenosine A2a receptor agonist, may excite the fetal carotid bodies. This study was designed to determine 1) whether CGS stimulates fetal breathing and 2) whether sinoaortic denervation abolishes CGS-induced tachycardia. In eight intact fetuses (>0.8 term), intra-arterial CGS infusion (6 μg ⋅ min−1 ⋅ kg estimated fetal wt−1) increased mean arterial [Formula: see text] by 3–7 Torr, reduced fetal arterial[Formula: see text] by 2–5 Torr, and produced a mild metabolic acidemia. Heart rate increased from 154 ± 7 (control) to 249 ± 12 beats/min, but mean arterial pressure was not significantly affected. CGS initially increased the frequency, amplitude, and incidence of fetal breathing, but this hyperpnea was followed by prolonged respiratory depression that was not reversed with blockade of adenosine A1 receptors. Denervation of both carotid bodies together with interruption of the vagi abolished the hyperpnea without altering the respiratory depression or the maximum rise in heart rate. We conclude that CGS induces 1) tachycardia by a mechanism independent of the peripheral arterial chemoreceptors, 2) hyperpnea by stimulating peripheral adenosine A2areceptors, and 3) respiratory depression by activating central A2a receptors.

Dose-dependent Respiratory Depression by Remifentanil in the Rabbit Parabrachial Nucleus/Kölliker–Fuse Complex and Pre-Bötzinger Complex

2021 ◽  
Author(s):  
Barbara Palkovic ◽  
Jennifer J. Callison ◽  
Vitaliy Marchenko ◽  
Eckehard A. E. Stuth ◽  
Edward J. Zuperku ◽  
...  
Keyword(s):  
Respiratory Rate ◽  
Respiratory Depression ◽  
Receptor Agonist ◽  
Parabrachial Nucleus ◽  
Respiratory Drive ◽  
Remifentanil Infusion ◽  
Opioid Receptor Agonist ◽  
Bötzinger Complex ◽  
Dose Dependent ◽  
Partial Reversal

Background Recent studies showed partial reversal of opioid-induced respiratory depression in the pre-Bötzinger complex and the parabrachial nucleus/Kölliker–Fuse complex. The hypothesis for this study was that opioid antagonism in the parabrachial nucleus/Kölliker–Fuse complex plus pre-Bötzinger complex completely reverses respiratory depression from clinically relevant opioid concentrations. Methods Experiments were performed in 48 adult, artificially ventilated, decerebrate rabbits. The authors decreased baseline respiratory rate ~50% with intravenous, “analgesic” remifentanil infusion or produced apnea with remifentanil boluses and investigated the reversal with naloxone microinjections (1 mM, 700 nl) into the Kölliker–Fuse nucleus, parabrachial nucleus, and pre-Bötzinger complex. In another group of animals, naloxone was injected only into the pre-Bötzinger complex to determine whether prior parabrachial nucleus/Kölliker–Fuse complex injection impacted the naloxone effect. Last, the µ-opioid receptor agonist [d-Ala,2N-MePhe,4Gly-ol]-enkephalin (100 μM, 700 nl) was injected into the parabrachial nucleus/Kölliker–Fuse complex. The data are presented as medians (25 to 75%). Results Remifentanil infusion reduced the respiratory rate from 36 (31 to 40) to 16 (15 to 21) breaths/min. Naloxone microinjections into the bilateral Kölliker–Fuse nucleus, parabrachial nucleus, and pre-Bötzinger complex increased the rate to 17 (16 to 22, n = 19, P = 0.005), 23 (19 to 29, n = 19, P < 0.001), and 25 (22 to 28) breaths/min (n = 11, P < 0.001), respectively. Naloxone injection into the parabrachial nucleus/Kölliker–Fuse complex prevented apnea in 12 of 17 animals, increasing the respiratory rate to 10 (0 to 12) breaths/min (P < 0.001); subsequent pre-Bötzinger complex injection prevented apnea in all animals (13 [10 to 19] breaths/min, n = 12, P = 0.002). Naloxone injection into the pre-Bötzinger complex alone increased the respiratory rate to 21 (15 to 26) breaths/min during analgesic concentrations (n = 10, P = 0.008) but not during apnea (0 [0 to 0] breaths/min, n = 9, P = 0.500). [d-Ala,2N-MePhe,4Gly-ol]-enkephalin injection into the parabrachial nucleus/Kölliker–Fuse complex decreased respiratory rate to 3 (2 to 6) breaths/min. Conclusions Opioid reversal in the parabrachial nucleus/Kölliker–Fuse complex plus pre-Bötzinger complex only partially reversed respiratory depression from analgesic and even less from “apneic” opioid doses. The lack of recovery pointed to opioid-induced depression of respiratory drive that determines the activity of these areas. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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