Repinotan, a Selective 5-HT1A-R-Agonist, Antagonizes Morphine-Induced Ventilatory Depression in Anesthetized Rats

@article{Guenther2010RepinotanAS,
  title={Repinotan, a Selective 5-HT1A-R-Agonist, Antagonizes Morphine-Induced Ventilatory Depression in Anesthetized Rats},
  author={Ulf Guenther and Hermann Wrigge and Nils Ulrich Theuerkauf and Michael Boettcher and Georg Wensing and Joerg Zinserling and Christian Putensen and Andreas Hoeft},
  journal={Anesthesia \& Analgesia},
  year={2010},
  volume={111},
  pages={901–907}
}
BACKGROUND:Spontaneous breathing during mechanical ventilation improves arterial oxygenation and cardiovascular function, but is depressed by opioids during critical care. Opioid-induced ventilatory depression was shown to be counteracted in anesthetized rats by serotonin(1A)-receptor (5-HT1A-R)-agonist 8-OH-DPAT, which cannot be applied to humans. Repinotan hydrochloride is a selective 5-HT1A-R-agonist already investigated in humans, but the effects on ventilation and nociception are unknown… 
Selective 5-HT1A-R-agonist Repinotan Prevents Remifentanil-induced Ventilatory Depression and Prolongs Antinociception
TLDR
Repinotan prevented remifentanil-induced ventilatory depression in spontaneously breathing, anesthetized rats and prolonged the profound antinociception after discontinuation of remifENTanil infusion.
5-HT1A Receptor Agonist Befiradol Reduces Fentanyl-induced Respiratory Depression, Analgesia, and Sedation in Rats
TLDR
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.
Effects of cholinesterase inhibitors and serotonin-1A receptor agonists on morphine-induced ventilatory depression and antinociception in rats.
TLDR
It is suggested that activation of cholinergic or serotonergic (5-HT1A) mechanisms may be a useful therapeutic approach for morphine-induced ventilatory depression without loss of its analgesic action.
Central administration of CXCR4 antagonist prevents the development of peripheral neuropathic pain and modulates the spinal expression of neuropeptides and pro-inflammatory cytokines in mice: 9AP1-9
TLDR
Repinotan, a selective 5-HT1A-R-agonist, antagonizes morphine-induced ventilatory depression in anesthetized rats, while analgesia was not impaired and the expected ef fect could have been uncovered using a study design wih preliminary established opioid-induced respiratory depression and an additional loss of awareness.
Activation of 5-HT1A receptors in the preBötzinger region has little impact on the respiratory pattern
TLDR
Results suggest that the tachypneic effects of IV 8-OH-DPAT are due to receptors located outside of the areas the authors studied, and suggest that systemically administered selective serotonin agonists have been shown to reduce or prevent opioid-induced depression of breathing.
Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network
TLDR
It is concluded that hyperpolarization of MOR-expressing preBötC neurons alone does not phenocopy OIRD, and the effects of MOR activation are twofold: pre-inspiratory spiking is reduced and excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis.
Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network
TLDR
It is concluded that hyperpolarization of MOR-expressing preBötC neurons alone does not phenocopy OIRD, and the effects of MOR activation are twofold: 1) pre-inspiratory spiking is reduced and 2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis.
Averting Opioid-induced Respiratory Depression without Affecting Analgesia.
TLDR
None of the experimental drugs are adequate for therapeutic use in opioid-induced respiratory depression and all need further study of efficacy and toxicity, but all do highlight potential mechanisms of action and possible templates for further study and development.
Opioid-induced respiratory depression in humans: a review of pharmacokinetic-pharmacodynamic modelling of reversal.
TLDR
Model-based drug development is needed to design an 'ideal' reversal agent, one that is not influenced by opioid receptor kinetics, does not interfere with opioid analgesia, has a rapid onset of action with long-lasting effects, and is devoid of adverse effects.
Sources of Inspiration: A Neurophysiologic Framework for Understanding Anesthetic Effects on Ventilatory Control
TLDR
Until reliable means for reversing drug-induced Ventilatory depression are developed, prompt recognition of ventilatory insufficiency and initiation of resuscitative measures remain the keys to patient safety.
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