Dynorphin selectively augments the M-current in hippocampal CA1 neurons byan opiate receptor mechanism

Dynorphin selectively augments the M-current in hippocampal CA1 neurons by an opiate receptor mechanism. J. Neurophysiol. 82: 1768-1775, 1999. Most el ectrophysiological studies of opioids on hippocampal principal neurons have found indirect actions, usually through interneurons. However, our laborat ory recently found reciprocal alteration of the voltage-dependent K+ curren t, known as the M-current (I-M), by kappa and delta opioid agonists in CA3 pyramidal neurons. Recent ultrastructural studies have revealed postsynapti c delta opiate receptors on dendrites and cell bodies of CA1 and CA3 hippoc ampal pyramidal neurons (HPNs). Reasoning that previous electrophysiologica l studies may have overlooked voltage-dependent postsynaptic effects of the opioids in CA1, we reevaluated their role in CA1 HPNs using the rat hippoc ampal slice preparation for intracellular current-and voltage-clamp recordi ng. None of the delta and mu receptor-selective opioids tested, including { D-Pen(2,5) -enkephalin (DPDPE), {D-Ala(2)}-deltorphin LI (deltorphin), {D-A la(2), NMe-Phe(4), Gly-ol}-enkephalin (DAMGO), and {D-Ala(2), D-Leu(5)} enk ephalin (DADLE), altered membrane properties such as I-M or Ca2+-dependent spikes in CAI HPNs. The nonopioid, Des-Tyr-dynorphin (D-T-dyn), also had no effect. By contrast, dynorphin A (1-17) markedly increased I-M at low conc entrations and caused an outward current at depolarized membrane potentials . The opioid antagonist naloxone and the re receptor antagonist nor-binalto rphimine (nBNI) blocked the I-M effect. However, the kappa-selective agonis ts U69,593 and U50,488h did not significantly alter I-M amplitudes when ave raged over all cells tested, although occasional cells showed an I-M increa se with U50,488h. Our results suggest that dynorphin A postsynaptically mod ulates the excitability of CA1 HPNs through opiate receptors linked to volt age-dependent K+ channels. These findings also provide pharmacological evid ence for a functional kappa opiate receptor subtype in rat CA1 HPNs but lea ve unanswered questions on the role of delta receptors in CA1 HPNs.