Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro

1 The rostral ventromedial medulla (RVM) is thought to play a crucial role in the antinociceptive actions of cannabinoids. This study examined the act ions of the cannabinoid receptor agonist, WIN55,212-2, on membrane properti es and GABAergic synaptic transmission in RVM neurons using whole cell patc h clamp recordings in brain slices. 2 WIN55,212-2 (3 mu M) had no effect on membrane K+ conductance of primary or secondary RVM neurons. Primary neurons responded to the kappa-opioid rec eptor agonist U69,593 (300 nM-1 mu M). Secondary neurons responded to the m u,delta-opioid receptor agonist met-enkephalin (10 mu M). 3 WIN55,212-2 reduced the amplitude of electrically evoked (GABAergic) inhi bitory postsynaptic currents (IPSCs) in all neurons (58%, pEC(50) = 6.21 +/ - 0.1). The inhibition was reversed by the CB1 receptor selective antagonis t, SR141716 (3 mu M). WIN55,212-2 also produced relative facilitation of th e 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 distr ibutions or kinetics. 5 These results suggest that the antinociceptive actions of cannabinoids wi thin RVM are primarily due to presynaptic inhibition of GABAergic neurotran smission. The neuronal substrates of cannabinoid actions in RVM therefore d iffer from those of opioids, which have both pre- and postsynaptic inhibito ry actions.