The modulatory effects of methionine-enkephalin (M-ENK) and selective opioid-receptor agonists on GABA-activated whole-cell currents were investigated in neurons acutely dissociated from the superficial laminae of the rat spinal dorsal horn using nystatin-perforated patch recording configuration under voltage-clamp conditions. The results show that: (1) GABA acted on GABA(A) receptors and elicited inward Cl-currents (I-GABA) at -60 mV; (2) M-ENK depressed I-GABA in similar to65%,, of the tested neurons and potentiated I-GABA in similar to15% of the neurons tested; (3) the agonists of mu-, kappa-, and delta-opioid receptors-[D-Ala(2),N-Me-Phe(4),Gly(5)- ol]-enkephalin (DAMGO), dynorphin-A (Dyn-A), and [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE) also depressed the I-GABA, and the order of agonist potency was DAMGO > Dyn-A > DPDPE; and (4) naloxone blocked the inhibitory effects of M-ENK on I-GABA. The antagonists of mu-, kappa-, and delta-opioid receptors-beta-funaltrexamine (beta-FNA), nor-binaltorphimine (nor-BNI), and naltrindole (NTI) prevented the DAMGO-, Dyn-A-, and DPDPE-induced depression of I-GABA. The results suggest that M-ENK downregulates I-GABA principally through mu- and kappa-opioid receptors, and thus exerts its modulating effects indirectly on the transmission of noxious information at the spinal level. (C) 2003 Elsevier Inc. All rights reserved.