Non-opioid analgesics have been shown to elicit antinociception by an action upon central nervous system structures, in addition to their well known action upon peripheral tissues. Microinjection of metamizol (dipyrone), a widely used nonopioid analgesic, into the periaqueductal grey matter (PAG) of rats activates pain-modulating systems in the nucleus raphe magnus and inhibits spinal nociceptive neurons and the tail-flick reflex. Since these effects involve an activation of endogenous opioidergic systems, the possibility that metamizol induces opioid tolerance was investigated. Microinjection of metamizol into the ventrolateral PAG in awake rats induced antinociception, as demonstrated in the heat-elicited tail flick and hot plate tests. When microinjected into the ventrolateral PAG twice daily for 2 days, metamizol induced tolerance, i.e. a progressive loss of its antinociceptive effect. In contrast to rats repeatedly microinjected with saline, metamizol-tolerant rats were also tolerant to morphine microinjection into the same PAG site, and displayed signs of opioid withdrawal upon systemic administration of naloxone. These and other results suggest that metamizol activates endogenous opioid systems and that nonopioid analgesics may, by an action upon the central nervous system, lead to opioid tolerance and the risk of opioid withdrawal.