Opioid and psychostimulant drugs have long been used for the relief of chronic pain in the clinical situation. Animal studies confirm that these drugs alleviate persistent or tonic pain. Little is known, however, about the neural systems underlying the suppression of tonic pain except that they are different from those mediating the suppression of phasic (i.e., sharp and short-lasting) pain. Although spinal and brainstem-descending pain suppression mechanisms play a role in mediating the inhibition of tonic pain, it appears that this response is additionally mediated by the activation of mechanisms lying rostral to the brainstem. Recent studies suggest that the activation of mesolimbic dopamine (DA) neurons, arising from the cell bodies of the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAcc), plays an important role in mediating the suppression of tonic pain. Other studies suggest that this pain-suppression system involving the activation of mesolimbic DA neurons is naturally triggered by exposure to stress, through the endogenous release of opioids and substance P (SP) in the midbrain.