Cellular and metabolic tolerance to an opioid narcotic in mouse brain.

1. Running activity and brain levorphanol concentration were measured in nontolerant and tolerant mice given various doses of (3)H-levorphanol.2. The principal factor responsible for tolerance in the mouse is a loss of sensitivity to the narcotic drug at the cellular level in brain; despite adequate brain concentrations, the pharmacological effects are diminished or absent.3. There is also metabolic tolerance; a given dose establishes a lower brain concentration in tolerant than in non-tolerant animals.4. The two kinds of tolerance are distinguished here and the contribution of each is assessed.