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In the NY1DD mice, naloxone (i.c.v.) possessed \u2248300-fold greater potency than morphine (i.c.v.). Other opioid antagonists (naltrexone, norbinaltorphimine, and naltrindole) were substantially less effective in producing analgesia. Naloxone and morphine were synergistic in NY1DD mice, suggesting different receptor systems. Microarray analysis suggested naloxone-induced down-regulation of the CC chemokine receptor (CCR)5 in NY1DD mice but not in control mice. Pretreatment of control mice with CC chemokine ligand 5 [CCL5 (RANTES)] enabled naloxone to produce analgesia similar to that observed in NY1DD mice. Mu opioid receptor knockout mice treated similarly also displayed analgesia. That the effect of CCL5 was specifically related to CCR5 and\/or CCR1 activation was demonstrated by antagonism of analgesia with the chemokine antagonist methionylated RANTES. Similar antagonism of naloxone-induced analgesia also was observed when NY1DD mice were pretreated with methionylated RANTES. These results indicate that CCR5\/CCR1 receptors are directly or indirectly involved in analgesia produced by naloxone. The present study suggests that naloxone may be clinically useful in the treatment of pain associated with sickle cell disease and other disorders involving inflammation.<\/jats:p>","DOI":"10.1073\/pnas.0700295104","type":"journal-article","created":{"date-parts":[[2007,3,27]],"date-time":"2007-03-27T23:41:55Z","timestamp":1175038915000},"page":"6061-6065","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["Naloxone acts as a potent analgesic in transgenic mouse models of sickle cell anemia"],"prefix":"10.1073","volume":"104","author":[{"given":"Mary M.","family":"Lunzer","sequence":"first","affiliation":[{"name":"*Department of Medicinal Chemistry, College of Pharmacy, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Yekkirala","sequence":"additional","affiliation":[{"name":"*Department of Medicinal Chemistry, College of Pharmacy, 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