VOLTAGE-DEPENDENT EFFECTS OF OPIOID-PEPTIDES ON HIPPOCAMPAL CA3 PYRAMIDAL NEURONS IN-VITRO

Opioid peptides, and especially the dynorphins, have been localized to several circuits in the CA3 hippocampal region, yet electrophysiologi cal studies often find mixed effects of opiates on the excitability of CA3 neurons. Reasoning that these mixed effects might involve voltage -dependent actions, we tested the effect of several opiates on CA3 pyr amidal neurons using single-electrode voltage-clamp recording in a sli ce preparation of rat hippocampus. In most CA3 neurons, the voltage-de pendent K+ current known as the M-current (I-M) was uniquely sensitive to the opioid peptides, with the direction of response dependent upon the opiate type and concentration. Thus, an opiate selective for kapp a receptors, U-50,488H, significantly augmented I-M. The kappa-selecti ve agonists dynorphin A and dynorphin B, which exist in messy fiber af ferents to CA3 pyramidal neurons, also markedly augmented I-M at low c oncentrations (20-100 nM). By contrast, dynorphin A at higher concentr ations (1-1.5 mu M) often reduced I-M. Similarly, several opiates [e.g ., D-Ala(2),D-Leu(5)-enkephalin: (DADL), [D-Pen(2,5)]-enkephalin (DPDP E)] known to act on the delta receptor subtypes reduced the M-current, with partial reversal of this effect by naloxone. Neither the selecti ve mu-receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol]enkephalin (DAMGO ) nor the nonopioid fragment of dynorphin, des-Tyr-dynorphin, consiste ntly altered I-M. These opiate effects on I-M were accompanied by chan ges in conductance and holding current consistent with their respectiv e effects on I-M. Dynorphin A did not measurably affect the Q-current, a conductance known to contribute to inward rectification in hippocam pal pyramidal neurons. The opiate effects on I-M were not altered by p retreatment with Cs+ (which blocks I-Q) or Ca2+ channel blockers. The opposing-effects of the dynorphins (both A and B) and DADL on I-M were antagonized by naloxone (1-3 mu M), and the dynorphin-induced augment ations of I,were usually reversed by the kappa receptor antagonist nor binaltorphimine. These results suggest that the opiates can have oppos ing effects on the same voltage-dependent K+ channel type (the M chann el) in the rat CA3 pyramidal neuron, with the direction of the respons e depending on which receptor subtype is activated. These data not onl y help explain the mixed effects of opiates seen in other studies, but also suggest a potential postsynaptic function for the endogenous opi ates contained in the CA3 messy fibers.