1. The actions of the neuropeptide nociceptin on the calcium channel currents (I(Ba)) of acutely dissociated rat periaqueductal grey (PAG) neurons were examined using whole-cell patch clamp techniques. These effects were compared with those of opioid receptor agonists and the GABA(B) receptor agonist baclofen. 2. Neurons from young adult rats (23 to 56 days old) expressed predominantly ω-conotoxin GVIA (N-type)- and ω-agatoxin IVA (P/Q-type)-sensitive I(Ba), together with smaller amounts of nimodipine-sensitive current and current resistant to all three blockers. There was proportionately more N-type I(Ba) in neurons from female rats and proportionately more resistant current in neurons from male rats. 3. Nociceptin (EC50, 5 nM) and baclofen (EC50, 0.8 μM) inhibited I(Ba) in all PAG neurons, while the opioid agonist methionine enkephalin (met-enkephalin; 300 nM-10 μM) inhibited I(Ba) in 40% of neurons. The effects of met-enkephalin were reversed by the μ-opioid antagonist CTAP, and mimicked by the μ-opioid agonist DAMGO (300 nM-3 μM). The δ-opioid agonists DPDPE and deltorphin II, and the κ-opioid agonist U69583, did not affect I(Ba) in any neuron. The actions of nociceptin were not mimicked or blocked by the opioid antagonist naloxone or the nociceptin analogue [desPhe1]-nociceptin. 4. The effects of nociceptin and baclofen on I(Ba) were blocked by pretreatment of the neurons with pertussis toxin (500 ng ml-1, 8 h). 5. Nociceptin predominantly inhibited the N-type (EC50, 2 nM; maximum inhibition, 50%) and P/Q-type (EC50, 7 nM; maximum inhibition, 33%) I(Ba) while having little effect on the L-type and R-type I(Ba). 6. These results are consistent with the previously described actions of nociceptin, baclofen and μ-opioids in PAG slices, whereby they couple to increases in an inwardly rectifying K+ conductance. These agonists thus have the potential to modulate the function of PAG neurons via a number of different cellular effecters.