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Ventilation in morphine-maintained rhesus monkeys. I: Effects of naltrexone and abstinence-associated withdrawal
1Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, USA.
Abstract:
The effects of naltrexone on ventilation were examined in three rhesus monkeys maintained on 3.2 mg/kg/day morphine. Before the onset of the daily morphine-dosing regimen, naltrexone had only modest effects on ventilation; a dose of 32 mg/kg increased ventilatory rate in the presence of normal air to 36 +/- 1 breaths/min, from a baseline rate of 25 +/- 1 breaths/min. Naltrexone did not affect other measures of ventilation in the presence of normal air or 5% CO2. Subsequent to the onset of the daily morphine injection regimen, naltrexone dose-dependently increased ventilatory rate at doses 4 orders of magnitude lower (0.001-0.01 mg/kg) than those effective in nondependent monkeys. A dose of 0.01 mg/kg naltrexone in morphine-maintained monkeys increased ventilatory rate in the presence of normal air to 52 +/- 4 breaths/min. Naltrexone also dose-dependently increased ventilatory rate in the presence of 3% and 5% CO2; tidal volume was not affected by naltrexone administration. Doubling the maintenance dose of morphine to 6.4 mg/ kg/day further increased the ventilatory effects of naltrexone. Withholding the maintenance dose of morphine also increased ventilatory rate without affecting tidal volumes, in a manner similar to that seen after naltrexone administration. These results are consistent with the view that changes in ventilation can be used to measure precipitated and abstinence-associated opioid withdrawal in monkeys.
Insights
Naltrexone significantly increases ventilation in morphine-dependent monkeys at very low doses, indicating its utility in measuring opioid withdrawal. This effect is amplified by higher morphine doses and withdrawal itself.
Area of Science:
- Pharmacology
- Neuroscience
- Respiratory Physiology
Background:
- Opioid dependence and withdrawal significantly impact respiratory function.
- Naltrexone is an opioid antagonist used in addiction treatment.
- Understanding naltrexone's effects on ventilation is crucial for managing opioid withdrawal.
Purpose of the Study:
- To investigate the effects of naltrexone on ventilation in morphine-dependent rhesus monkeys.
- To determine if naltrexone's effects differ between dependent and non-dependent states.
- To assess naltrexone's potential as a measure of opioid withdrawal.
Main Methods:
- Three rhesus monkeys were administered daily morphine (3.2 mg/kg).
- Naltrexone's effects on ventilatory rate and tidal volume were measured before and after morphine dependence.
- Ventilation was assessed in normal air and with elevated CO2 levels.
Main Results:
- Naltrexone had minimal effects on ventilation in non-dependent monkeys.
- In morphine-dependent monkeys, naltrexone dose-dependently increased ventilatory rate at significantly lower doses.
- Increased morphine dosage and morphine withdrawal potentiated naltrexone's ventilatory effects.
Conclusions:
- Naltrexone's potentiation of ventilation in dependent monkeys suggests its use in measuring opioid withdrawal.
- Changes in ventilation can serve as an indicator for precipitated and abstinence-associated opioid withdrawal in primates.
- These findings support naltrexone's role in the study of opioid dependence and withdrawal.