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Microinjection of metamizol (dipyrone), a widely used nonopioid analgesic, into the periaqueductal grey matter (PAG) of rats activates pain\u2010modulating systems in the nucleus raphe magnus and inhibits spinal nociceptive neurons and the tail\u2010flick 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\u2010elicited tail flick and hot plate tests. When microinjected into the ventrolateral PAG twice daily for 2\u2003days, metamizol induced tolerance, i.e. a progressive loss of its antinociceptive effect. In contrast to rats repeatedly microinjected with saline, metamizol\u2010tolerant 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.<\/jats:p>","DOI":"10.1046\/j.1460-9568.2000.00295.x","type":"journal-article","created":{"date-parts":[[2003,3,6]],"date-time":"2003-03-06T14:28:18Z","timestamp":1046960898000},"page":"4074-4080","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Opioid tolerance induced by metamizol (dipyrone) microinjections into the periaqueductal grey of rats"],"prefix":"10.1111","volume":"12","author":[{"given":"V\u00edctor","family":"Tortorici","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horacio","family":"Vanegas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,10,9]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0014-2999(98)00026-0"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1987.67.1.67"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1998.79.2.677"},{"key":"e_1_2_6_5_1","first-page":"1381","article-title":"Effects of intrathecal or intracerebral administration of nonsteroidal ant\u2010inflammatory drugs on a C\u2010fiber reflex in rats","volume":"281","author":"Bustamante D.","year":"1997","journal-title":"J. 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