Physical dependence and tolerance development after chronic exposure to low levels of morphine in the rat

A sustained-release delivery system containing ¹⁴C-morphine was implanted subcutaneously in rats. Measurement of urinary excretion of ¹⁴C suggested a steady state release of approximately 640 μg ¹⁴C morphine/day during a 10-day test period. Tolerance developed rapidly to the analgetic effects produced by an injected ED₉₅ dose of morphine sulfate in implanted rats tested on the hot-plate. Physical dependence, determined by naloxone-precipitated abstinence behavior, was evident in rats at 24 hr. Morphine dosage was estimated to be as low as 2.5 mg/kg/day. Peak abstinence behavior was observed on Day 4. However, naloxone-precipitated withdrawal signs were markedly diminished by Day 6 and essentially absent by Day 8. These results are discussed with reference to the suggestion that metabolic changes, occuring during chronic exposure to morphine, may explain the lack of abstinence behavior during a time when maximal concentrations of urinary morphine were observed and a high degree of tolerance was manifest.