Acute dependence on, but not tolerance to, heroin and morphine as measured by respiratory effects in rhesus monkeys

Eur J Pharmacol. 2000 Jun 9;398(1):121-30. doi: 10.1016/s0014-2999(00)00279-x.


Acute dependence on and tolerance to heroin and morphine were assessed in rhesus monkeys using measures of respiration. Respiratory frequency (f) and minute volume (V(e)) were measured in monkeys breathing air or 5% CO(2) in air using a pressure-displacement plethysmograph. Cumulative doses of naltrexone (0.0001-1.0 mg/kg, i.m) did not alter these parameters in untreated monkeys. Twenty-four hours after a cumulative dose of heroin (1 mg/kg, i.m.), naltrexone produced an increase in both f and V(e) when monkeys were breathing air or 5% CO(2). Following 1 to 3 days of treatment with heroin (0.5 mg/kg/day, i.m.) or morphine (16 mg/kg/day, i.m.), naltrexone produced an increase in f and V(e) that was related to the dose of naltrexone and the number of days of agonist administration. Two days following termination of heroin administration, naltrexone-induced respiratory stimulation declined and had disappeared completely by the fifth day. In tolerance studies, heroin (0.032-0.5 mg/kg, i.m.) and morphine (1-16 mg/kg, i. m.) were injected cumulatively each day for three consecutive days. These drugs suppressed f and V(e) to nearly the same extent on day 3 as they had on day 1 of administration. These results suggest that dependence to morphine and heroin can be measured under conditions of acute 1 to 3 day administration conditions in primates using f and V(e) as reliable and quantitative indicators of opioid withdrawal. Under these conditions, tolerance does not occur.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Carbon Dioxide / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Tolerance
  • Heroin / pharmacology*
  • Heroin Dependence / physiopathology*
  • Macaca mulatta
  • Morphine / pharmacology*
  • Morphine Dependence / physiopathology*
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Respiration / drug effects*
  • Time Factors


  • Analgesics, Opioid
  • Narcotic Antagonists
  • Carbon Dioxide
  • Naltrexone
  • Heroin
  • Morphine