Rationale <p>Interoceptive sensations elicited by psychoactive substances can acquire incentive motivational properties via learned associations with other reinforcers. Moreover, interoceptive drug states have been linked to and can predict their own reinforcing action.</p> Objectives <p>Given these interactions between the interoceptive and reinforcing properties of drugs, the current study tested the hypothesis that the learned significance of an interoceptive drug stimulus can enhance its reinforcing action.</p> Methods <p>To investigate this, the interoceptive stimulus properties of morphine were trained as a positive or negative occasion setter that signaled the presence or absence of an appetitive (auditory stimulus-sucrose) association, respectively. Then, intravenous morphine self-administration was conducted to assess aspects of morphine reinforcement.</p> Results <p>When the interoceptive effects of morphine were learned to facilitate the activation of an appetitive Pavlovian association, it acquired reinforcing properties such that it promoted robust acquisition of lever discrimination, enhanced morphine-seeking under escalating response requirements, and maintained responding in the absence of reinforcement. Conversely, when the interoceptive properties of morphine were learned to facilitate the suppression of the appetitive association, it acquired inhibitory properties, such that it attenuated responding across extinction as well as during reinstatement assessment compared to controls.</p> Conclusions <p>Thus, through mechanisms of associative learning, in addition to resolving reward-predictive stimulus ambiguity, the interoceptive effects of morphine can acquire altered reinforcing properties. These findings highlight that the learned significance of a drug’s interoceptive effects can alter its subsequent reinforcing efficacy, and that occasion setting serves as a mechanism of learning through which this can occur.</p>