A benzodiazepine antagonist inhibits the cerebral metabolic and respiratory depressant effects of fentanyl.
It is reported that benzodiazepines such as diazepam will stimulate the opiate receptor system and that B-carboline drugs, which are benzodiazepine antagonists, may interact with opiate receptors directly. The ability of 3-hydroxymethyl-B-carboline (3-HMC) to antagonize several parameters of fentanyl anesthesia was tested here in rats. Fentanyl (25 and 100 micrograms/kg iv) produced dose dependent depression of cerebral blood flow (CBF), measured by radioactive microspheres, and cerebral oxygen consumption (CMRO2). These effects were significantly inhibited by 10 mg/kg 3-HMC iv. To test for the specificity of this effect, 3-HMC was also given to rats ventilated with inspire concentrations of 2% halothane. Halothane depressed CMRO2 equally in 3-HMC and vehicle treated rats, indicating no significant effect of the benzodiazepine antagonist. Blood pressure was increased in 3-HMC compared to vehicle treated animals during both fentanyl and halothane anesthesia. CBF was increased in 3-HMC vs vehicle treated rats during halothane anesthesia but this could be accounted for by the elevated blood pressure and lack of cerebral autoregulation rather than a direct cerebrovascular effect. 3-HMC decreased the sleep time and respiratory depressant effects of fentanyl but enhanced the analgesic effects of the opiate, as measured by time to respond to a hot plate stimulus. These results indicate that 3-HMC has the ability to specifically antagonize fentanyl anesthesia. These effects may be produced by an action of 3-HMC at the benzodiazepine receptor and/or by an action of the B-carboline at opioid receptors.
D000758:Anesthesia; D000818:Animals; D001569:Benzodiazepines / Q000037:antagonists & inhibitors*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D005283:Fentanyl / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012119:Respiration / Q000187:drug effects*
D002243:Carbolines; D007211:Indoles; D001569:Benzodiazepines; C031516:3-hydroxymethyl-beta-carboline; D005283:Fentanyl