1. The overall effect of the μ-opioid receptor agonist DAMGO (Tyr-D-Ala-Gly-MePhe-Gly-ol) on ventrolateral periaqueductal grey (PAG) neurons in brain slices was studied using the whole-cell patch-clamp recording technique. 2. Under current-clamp conditions, DAMGO (1 μM) increased cell firing in many PAG neurons even though the opioid induced hyperpolarization and inhibited excitatory postsynaptic potentials (EPSPs) in these cells. 3. The increase in cell activity by DAMGO was observed in both transverse and horizontal slices. The increase persisted when the membrane potential was re-depolarized to the control level. Thus, different planes of sections or the removal of Na+ channel inactivation could not account for the observation. 4. The GABA antagonist bicuculline caused cell firing, mimicking the excitatory effect of DAMGO. Unlike DAMGO, however, bicuculline depolarized PAG cells. 5. Under voltage-clamp conditions, with the same driving force, the evoked inhibitory postsynaptic currents (IPSCs) in these neurons were 2.3 times larger than the evoked excitatory postsynaptic currents (EPSCs). Furthermore, DAMGO inhibited IPSCs by 60.7% while it inhibited EPSCs by 35.3%. 6. We propose that the overall effect of an opioid depends on the dynamic balance of its excitatory and inhibitory actions. In the PAG, the blockade of the inhibitory drive of GABAergic inputs by DAMGO is large. It overcomes the DAMGO-induced hyperpolarization and inhibition of EPSCs and thus results in the excitation of these neurons.
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