Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro

The midbrain periaqueductal gray (PAG) is a major site of cannabinoid-media ted analgesia in the central nervous system. In the present study, we exami ned the actions of cannabinoids on rat PAG neurons in vitro. In brain slice s, superfusion of the cannabinoid receptor agonist WIN55,212-2 inhibited el ectrically evoked inhibitory and excitatory postsynaptic currents in all PA G neurons. The endogenous cannabinoid anandamide inhibited evoked inhibitor y postsynaptic currents in the presence of the anandamide transport inhibit or AM404, but not in its absence. The stable anandamide analog R1-methanand amide also inhibited evoked inhibitory postsynaptic currents. WIN55,212-2 r educed the rate of spontaneous miniature inhibitory postsynaptic currents i n normal and Ca2+-free solutions, but had no effect on their amplitude dist ributions or kinetics. The WIN55,212-2-induced decrease in miniature inhibi tory postsynaptic current rate was concentration dependent (EC50 = 520 nM). The effects of cannabinoids were reversed by the CB1 receptor antagonist S R141716. WIN55,212-2 produced no change in membrane current or conductance in PAG neurons in brain slices and had no effect on Ca2+-channel currents i n acutely isolated PAG neurons. These findings suggest that cannabinoids ac t via CB1 receptors to inhibit GABAergic and glutamatergic synaptic transmi ssion in rat PAG, although the efficacy of endogenous cannabinoids is likel y to be limited by uptake and breakdown. Like mu-opioids, cannabinoids act to reduce the probability of transmitter release from presynaptic terminals via a Ca2+-independent mechanism. In contrast to mu-opioids, cannabinoids have no direct postsynaptic actions on PAG neurons. Thus, cannabinoids and mu-opioids are likely to produce analgesia within PAG in part by different mechanisms.