Mechanism underlying increased neuronal activity in the rat ventrolateral periaqueductal grey by a mu-opioid

1. The overall effect of the mu-opioid receptor agonist DAMGO (Tyr-D-Ala-Gl y-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 mu M) increased cell firing in many PAG neurons even though the opioid induced hyperpolarization and inhib ited excitatory postsynaptic potentials (EPSPs) in these cells. 3. The increase in cell activity by DAMGO was observed in both transverse a nd horizontal slices. The increase persisted when the membrane potential wa s re-depolarized to the control level. Thus, different planes of sections o r the removal of Na+ channel inactivation could not account for the observa tion. 4. The GABA antagonist bicucullline caused cell firing, mimicking the excit atory effect of DAMGO. Unlike DAMGO, however, bicuculline depolarized PAG c ells. 5. Under voltage-clamp conditions, with the same driving force, the evoked inhibitory postsynaptic currents (IPSCs) in these neurons were 2.3 times la rger 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 b alance of its excitatory and inhibitory actions. In the PAG, the blockade o f the inhibitory drive of GABAergic inputs by DAMGO is large. It overcomes the DAMGO-induced hyperpolarization and inhibition of EPSCs and thus result s in the excitation of these neurons.