1 Cannabinoid receptor agonists elicit analgesic effects in acute and chronic pain states via spinal and supraspinal pathways. We investigated whether the combination of a cannabinoid agonist with other classes of antinociceptive drugs exerted supra-additive (synergistic) or additive effects in acute pain models in mice. 2 The interactions between the cannabinoid agonist CP55,940, a 2 -adrenoceptor agonist dexmedetomidine and m-opioid receptor agonist morphine were evaluated by isobolographic analysis of antinociception in hot plate (551C) and tail flick assays in conscious male Swiss mice. Drug interactions were examined by administering fixed-ratio combinations of agonists (s.c.) in 1 : 1, 3 : 1 and 1 : 3 ratios of their respective ED 50 fractions. 3 CP55,940, dexmedetomidine and morphine all caused dose-dependent antinociception. In the hot plate and tail flick assays, ED 50 values (mg kg À1 ) were CP55,940 1.13 and 0.51, dexmedetomidine 0.066 and 0.023, and morphine 29.4 and 11.3, respectively. Synergistic interactions existed between CP55,940 and dexmedetomidine in the hot plate assay, and CP55,940 and morphine in both assays. Additive interactions were found for CP55,940 and dexmedetomidine in the tail flick assay, and dexmedetomidine and morphine in both assays. 4 Thus, an a 2 -adrenoceptor agonist or m opioid receptor agonist when combined with a cannabinoid receptor agonist showed significant synergy in antinociception in the hot plate test. However, for the tail flick nociceptive response to heat, only cannabinoid and m opioid receptor antinociceptive synergy was demonstrated. If these results translate to humans, then prudent selection of dose and receptorspecific agonists may allow an improved therapeutic separation from unwanted side effects.