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Naloxone-induced cardiovascular depression in rats that had received chronic morphine-treatment
Abstract:
1. Cardiovascular changes in response to intravenous injection of naloxone were studied in pentobarbitone-anaesthetized rats which had been given morphine in their drinking water for 1-21 days. The mechanisms of the observed changes were investigated in intact animals and in isolated hearts and tail arteries. 2. In rats that had received chronic morphine-treatment, intravenous administration of naloxone caused immediate decreases in blood pressure, heart rate, left ventricular pressure and dLVP/dtmax which were followed by the occurrence of atrial or ventricular extrasystoles and other signs of opiate withdrawal such as faecal passage and muscle twitching. 3. The intensities of the naloxone-precipitated cardiovascular changes were directly related to the duration of chronic morphine pretreatment, reaching statistically significant levels on day 2 or 3 and maximal levels on day 7 or 14. This phenomenon disappeared on days 3 to 14 following opiate withdrawal in animals which had been treated previously with morphine for 21 days. 4. Either atropine or clonidine pretreatment significantly prevented the occurrence of faecal passage or muscle twitching during naloxone-precipitated opiate withdrawal. However, clonidine, but not atropine or yohimbine, abolished the decreases in various haemodynamic parameters. The occurrence of cardiac extrasystoles was not affected. 5. In isolated heart or tail artery preparations from chronically morphine-treated rats, naloxone administration did not elicit reactions which differed from those of the preparations from naive animals. These findings suggest that under pentobarbitone anaesthesia, the cardiovascular systems of rats that had received chronic morphine treatment exhibit inhibitory, instead of excitatory, reactions to naloxone-precipitated opiate withdrawal.
Insights
Chronic morphine treatment in rats alters cardiovascular responses to naloxone, causing withdrawal symptoms and hemodynamic changes. These effects intensify with treatment duration but resolve after cessation, suggesting inhibitory cardiovascular reactions.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Neuroscience
Background:
- Chronic opioid administration can lead to physical dependence and withdrawal syndromes.
- Naloxone is a standard opioid antagonist used to precipitate withdrawal.
- Cardiovascular responses during opioid withdrawal are complex and not fully understood.
Purpose of the Study:
- To investigate cardiovascular changes in rats following chronic morphine exposure and acute naloxone administration.
- To explore the underlying mechanisms of these cardiovascular alterations and withdrawal symptoms.
- To determine the role of specific neurotransmitters in naloxone-precipitated withdrawal.
Main Methods:
- Rats received morphine in drinking water for 1-21 days, followed by intravenous naloxone administration.
- Cardiovascular parameters (blood pressure, heart rate, ventricular pressure) were monitored in anesthetized rats.
- Isolated heart and tail artery preparations were used to assess direct tissue responses.
- Pretreatment with atropine, clonidine, or yohimbine was employed to investigate mechanisms.
Main Results:
- Naloxone induced significant decreases in blood pressure, heart rate, and cardiac contractility in chronically morphine-treated rats.
- These cardiovascular changes and withdrawal signs (e.g., muscle twitching) were dose- and duration-dependent.
- Clonidine pretreatment attenuated hemodynamic changes, while atropine and yohimbine did not.
- Isolated organ preparations showed no differential response to naloxone, suggesting central mechanisms.
Conclusions:
- Chronic morphine treatment in rats leads to inhibitory cardiovascular responses to naloxone-precipitated withdrawal under anesthesia.
- The observed hemodynamic changes are likely mediated by central mechanisms, possibly involving alpha-2 adrenergic pathways.
- These findings highlight the complex interplay between chronic opioid use, withdrawal, and cardiovascular regulation.