Dopamine1 receptor agonists reverse opioid respiratory network depression, increase CO2 reactivity.
ABSTRACT In adult pentobarbital-anesthetized and unanesthetized decerebrate cats, the D(1)R agonists (6-chloro-APB, SKF-38393, dihydrexidine) given intravenously restored phrenic nerve and vagus nerve respiratory discharges and firing of bulbar post-inspiratory neurons after the discharges were abolished by the micro-opioid receptor agonist fentanyl given intravenously. Reversal of opioid-mediated discharge depression was prevented by the D(1)R antagonist SCH23390. Iontophoresis of the micro-opioid receptor agonist DAMGO depressed firing of medullary bulbospinal inspiratory neurons. Co-iontophoresis of SKF-38393 did not restore firing and had no effect on bulbospinal inspiratory neuron discharges when applied alone. The D(1)R agonists given intravenously prolonged and intensified phrenic nerve and bulbospinal inspiratory neuron discharges. They also increased reactivity to CO(2) by lowering the phrenic nerve apnea threshold and shifting the phrenic nerve-CO(2) response curve to lower et(CO(2)) levels. Intravenous fentanyl on the other hand decreased CO(2) reactivity by shifting the phrenic nerve apnea threshold and the response curve to higher et(CO(2)) levels. Fentanyl effects on reactivity were partially reversed by D(1)R agonists.
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ABSTRACT: Hypothyroidism can lead to depressed breathing. We determined if propylthiouracil (PTU)-induced hypothyroidismin hamsters (HH) altered dopamine D1 receptor expression, D1 receptor-modulated ventilation, and ventilatory chemoreflex activation by hypoxia or hypercapnia. Hypothyroidism was induced by administering 0.04% PTU in drinking water for 3 months. Ventilation was evaluated following saline or 0.25mg/kg SCH 23390,a D1 receptor antagonist, while awake hamsters breathed normoxic (21% O(2) in N(2)), hypoxic (10% O(2)in N(2)) and hypercapnic (5% CO(2) in O(2))air. Relative to euthyroid hamsters (EH), HH exhibited decreased D1 receptor protein levels in carotid bodies, striatum, and hypothalamic paraventricular nucleus, but not in the nucleus tractus solitarius. Relative to EH, HH exhibited lower ventilation during exposure to normoxia, hypoxia, or hypercapnia, but comparable ventilatory responsiveness to chemoreflex activation. SCH23390 decreased ventilation of EH hamsters exposed to normoxia, hypoxia, and hypercapnia. In HH SCH23390 increased ventilation during baseline normoxia and did not affect ventilation during exposure to hypoxia and hypercapnia, resulting in reduced ventilatory responsivess to chemoreflex activation by hypoxia and hypercapnia. Furthermore, in HH D1 receptor protein levels are decreased in several brain regions and within the carotid bodies. Moreover, D1 receptor-modulation of breathing at rest and during gas exposures were depressed in EH but not HH.Brain research 07/2011; 1401:40-51. DOI:10.1016/j.brainres.2011.05.034 · 2.83 Impact Factor
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ABSTRACT: Previous studies indicate that dopamine modulates the excitability of the respiratory network and its susceptibility to depression by exogenous opioids, but the roles of different subtypes of dopamine receptor in these processes are still uncertain. In this study, D1-dopamine receptor (D1R) involvement in dopaminergic modulation of respiratory rhythm and mu-opioid receptor mediated depression were investigated in pentobarbital-anesthetized cats. Intravenous administration of the D1R blocker SCH-23390 (100-200 microg/kg) slowed phrenic nerve and expiratory neuron respiratory rhythms by prolonging the inspiratory and expiratory phases. Phrenic nerve discharge intensity also increased more gradually during the inspiratory phase. SCH-23390 (150 microg/kg) also enhanced dose-dependent depression of phrenic nerve and expiratory neuron excitability, as well as rhythm disturbances, produced by the mu-opioid receptor agonist fentanyl (2-20 microg/kg, i.v.). The results suggest an important role for the D1-subtype of receptor in respiratory rhythm modulation, and indicate that this type of receptor participates in dopaminergic compensatory mechanisms directed against opioid-mediated network depression.Respiratory Physiology & Neurobiology 02/2005; 145(1):13-22. DOI:10.1016/j.resp.2004.11.001 · 1.97 Impact Factor
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ABSTRACT: Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease) can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C02. In the other experiment, apneic threshold PaC02 was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit.Biological research 02/2007; 40(3):339-46. DOI:10.4067/S0716-97602007000400008 · 1.04 Impact Factor