Opioid potentiation of N-type Ca2+ channel currents via pertussis-toxin-sensitive G proteins in NG108-15 cells

Opioids have both inhibitory and stimulatory effects on neurotransmitter re lease. While the inhibitory effect has been ascribed to presynaptic inhibit ion of Ca2+ channels, the cellular mechanism underlying the stimulatory eff ect is not clear. In order to address this issue, we analyzed the effects o f [D-Ala(2), D-Leu(5)]-enkephalin (DADLE) on whole-cell Ba2+ currents (I-Ba ) through voltage-gated Ca2+ channels in NG108-15 neuroblastoma x glioma hy brid cells. Application of DADLE inhibited and washout of DADLE transiently potentiated I-Ba Furthermore, potentiation of I-Ba was elicited even in th e presence of DADLE, when inhibition was relieved by a large depolarizing p repulse. DADLE-induced potentiation, as well as inhibition, had both voltag e-sensitive and -insensitive components and was abolished by treatment with ICI174864, a delta-opioid antagonist, pertussis toxin (PTX) and omega-cono toxin GVIA. Potentiation developed over congruent to 3 min and took 5-20 mi n to recover, whereas inhibition was complete within 30 s and recovered wit hin 1 min. Although this potentiation should contribute to DADLE-induced de sensitization of Ca2+ channel inhibition, it was not the sole mechanism for desensitization. We conclude that the delta-opioid receptor exerts a dual action on N-type Ca2+ channels via PTX-sensitive G proteins, i.e., rapid in hibition followed by slowly developing potentiation.