Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstayrnof medical pain therapy remains drugs that have been around for decades, like non-steroidalrnanti-inflammatory drugs (NSAIDs), or opiates. However, adverse effects of opiates, particularly tolerance,rnlimit their clinical use. Several lines of investigations have shown that systemic (intraperitoneal)rnadministration of NSAIDs induces antinociception with some effects of tolerance. In this review,rnwe report that repeated microinjection of NSAIDs analgin, clodifen, ketorolac and xefocam intornthe central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphernmagnus in the following 4 days result in progressively less antinociception compared to the salinerncontrol testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to theserndrugs and cross-tolerance to morphine in male rats. These findings strongly support the suggestionrnof endogenous opioid involvement in NSAIDs antinociception and tolerance in the descendingrnpain-control system. Moreover, the periaqueductal grey-rostral ventro-medial part of medulla circuitrnshould be viewed as a pain-modulation system. These data are important for human medicine. Inrnparticular, cross-tolerance between non-opioid and opioid analgesics should be important in thernclinical setting.