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Vol. 57, Issue 2, 288-295, February 2000
Department of Pharmacology (C.W.V., M.C., E.E.B., M.J.C.) and the
Medical Foundation (M.J.C.), University of Sydney, Sydney, New South
Wales, Australia.
The midbrain periaqueductal gray (PAG) is a major site of
cannabinoid-mediated analgesia in the central nervous system. In the
present study, we examined the actions of cannabinoids on rat PAG
neurons in vitro. In brain slices, superfusion of the cannabinoid
receptor agonist WIN55,212-2 inhibited electrically evoked inhibitory
and excitatory postsynaptic currents in all PAG neurons. The
endogenous cannabinoid anandamide inhibited evoked inhibitory
postsynaptic currents in the presence of the anandamide transport
inhibitor AM404, but not in its absence. The stable anandamide analog
R1-methanandamide also inhibited evoked inhibitory postsynaptic
currents. WIN55,212-2 reduced the rate of spontaneous miniature
inhibitory postsynaptic currents in normal and Ca2+-free
solutions, but had no effect on their amplitude distributions or
kinetics. The WIN55,212-2-induced decrease in miniature inhibitory postsynaptic current rate was concentration dependent
(EC50 = 520 nM). The effects of cannabinoids were
reversed by the CB1 receptor antagonist SR141716.
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 in acutely isolated PAG neurons.
These findings suggest that cannabinoids act via CB1
receptors to inhibit GABAergic and glutamatergic synaptic transmission
in rat PAG, although the efficacy of endogenous cannabinoids is likely
to be limited by uptake and breakdown. Like µ-opioids, cannabinoids
act to reduce the probability of transmitter release from presynaptic
terminals via a Ca2+-independent mechanism. In contrast to
µ-opioids, cannabinoids have no direct postsynaptic actions on PAG
neurons. Thus, cannabinoids and µ-opioids are likely to produce
analgesia within PAG in part by different mechanisms.
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