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The possibility of the presence of chronic tolerance to the analgesic effect of prolactin and of dependence was tested. Repeated administration of prolactin resulted in the loss of analgesic activity, indicating the development of chronic tolerance. Neither a high dose of, or chronic treatment with prolactin followed by naloxone elicited any characteristic withdrawal signs, suggesting the absence of dependence. Similarly, abrupt withdrawal of prolonged prolactin treatment also did not elicit withdrawal signs. However, in the same model, the morphine-naloxone combination and spontaneous withdrawal of chronic morphine treatment produced characteristic withdrawal signs, namely jumping, wet shakes, and body tremor. The data support the view that tolerance and dependence can be dissociated from each other and that different mechanisms may operate in these phenomena. The absence of liability to dependence with prolactin strengthens the contention that prolactin may be a potential drug for combatting opiate dependence.