Electrophysiological studies in rats demonstrate that a subset of mesolimbic dopamine neurons that are initially inhibited by a noxious stimulation show ‘rebound’ excitation at the offset of the stimulus.Recent investigations using fast-scan cyclic voltammetry in rats show phasic dopamine release in the nucleus accumbens shell at the termination of a noxious tail pinch.Using neuroimaging in humans and rats, increased BOLD activity was detected at the offset of a brief noxious stimulus in the nucleus accumbens and in the anterior cingulate cortex.In Drosophila, rodents, and humans, relief of an acute painful stimulus is associated with conditioned reward learning.In rats, relief of ongoing pain promotes a conditioned place preference that requires opioid signaling in the anterior cingulate cortex and subsequent release of dopamine in the nucleus accumbens.