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