1. The rostral ventromedial medulla (RVM) is thought to play a crucial role in the antinociceptive actions of cannabinoids. This study examined the actions of the cannabinoid receptor agonist, WIN55,212-2, on membrane properties and GABAergic synaptic transmission in RVM neurons using whole cell patch clamp recordings in brain slices. 2. WIN55,212-2 (3 microM) had no effect on membrane K+ conductance of primary or secondary RVM neurons. Primary neurons responded to the kappa-opioid receptor agonist U69,593 (300 nM - 1 microM). Secondary neurons responded to the mu,delta-opioid receptor agonist met-enkephalin (10 microM). 3. WIN55,212-2 reduced the amplitude of electrically evoked (GABAergic) inhibitory postsynaptic currents (IPSCs) in all neurons (58%, pEC50=6.2+/-0.1). The inhibition was reversed by the CB1 receptor selective antagonist, SR141716 (3 microM). WIN55,212-2 also produced relative facilitation of the second IPSC to paired evoked IPSCs. 4. WIN55,212-2 and met-enkephalin reduced the rate of spontaneous miniature IPSCs in all cells (44 and 53%), but had no effect on their amplitude distributions or kinetics. 5. These results suggest that the antinociceptive actions of cannabinoids within RVM are primarily due to presynaptic inhibition of GABAergic neurotransmission. The neuronal substrates of cannabinoid actions in RVM therefore differ from those of opioids, which have both pre- and postsynaptic inhibitory actions.