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The first injection impaired sensorimotor responses and reduced body temperature, analgesia, and breath rate to a greater extent in females than in males; the second injection induced stronger effects in males while the third injection of AKB48 induced weaker responses in both sexes, suggesting emergence of tolerance. The CB<jats:sub>1<\/jats:sub> receptor antagonist NESS\u20100327 prevented the effects induced by repeated AKB48, confirming a CB<jats:sub>1<\/jats:sub> receptor\u2010mediated action. Blood AKB48 levels were higher in females than in males and repeated administration caused a progressive rise of AKB48 levels in both sexes, suggesting an inhibitory effect on cytochrome activity. 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