Buprenorphine is relatively resistant to reversal by naloxone. We tested the effect of various doses and infusion schemes of naloxone on buprenorphine-induced respiratory depression and compared the data with naloxone-reversal of morphine and alfentanil-induced respiratory depression. Both morphine and alfentanil were easily reversed by low doses of naloxone (0.4 mg). Increasing doses of naloxone caused a bell-shaped reversal curve of buprenorphine with maximal reversal at naloxone doses between 2 and 4 mg. However, reversal was short-lived. The bell-shaped reversal curve may be related to the existence of two mu-opioid receptor subtypes, one mediating the agonist effects of opioids at low dose, the other mediating antagonistic effects at high dose.