Naloxone-induced cardiovascular depression in rats that had received chronic morphine-treatment.

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.