Morphine and other opioids are the most effective prescription medications for the treatment of pain. Associated addiction and hyperalgesia, however, limits the clinical utility of these drugs. The present study aimed to determine the potential effectiveness of buspirone, a partial agonist at 5-hydroxytryptamine (5-HT, serotonin)-1A receptor in reducing morphine-induced addiction and hyperalgesia. We found that co-administration of buspirone with morphine inhibited reinforcing as well as hyperalgesic effects of morphine. Tolerance in motor depressant effects of morphine was also reversed. Effects of morphine on dopamine and serotonin metabolism in nucleus accumbens and caudate were also reversed by buspirone co-administration. Reinforcing, analgesic, and motor effects of nalbuphine, another opioid drug, were also monitored. Both low and high doses of nalbuphine produced reinforcing effects. High but not low doses produced sensitization. Moderate doses of nalbuphine did not produce reinforcement or sensitization like effects. Moderate doses of nalbuphine produced greater pain killing effects than smaller or higher doses. We also determined the effects of repeated administration of buspirone on memory, pain perception, and 5-HT1A receptor expression in brain regions associated with addiction and memory. Administration of buspirone at 1 mg/kg but not at 0.3 mg/kg or 0.1 mg/kg produced significant analgesic effects. Repeated administration of buspirone at doses of 0.1 and 1 mg/kg but not at 0.3 mg/kg produced hyperalgesia. Low buspirone dosage (0.1 mg/kg) improved, while higher dosages (0.3 and 1 mg/kg) impaired performance in Morris water maze. This was associated with the down-regulation of serotonin-1A receptors in the prefrontal cortex and hippocampus. The findings show an important role of 5-HT1A receptor in morphine abuse and hyperalgesia. It is suggested that clinicians should consider buspirone as adjunctive therapy with morphine to prevent its abuse during the treatment. Because higher but not lower doses of buspirone were found to impair cognition; lower doses may be preferably used to improve therapeutics in chronic pain.