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Journal of Neuroscience, Vol 14, 809-820, Copyright © 1994 by Society for Neuroscience
Voltage-dependent effects of opioid peptides on hippocampal CA3 pyramidal neurons in vitro
SD Moore, SG Madamba, P Schweitzer and GR Siggins
Scripps Research Institute, Department of Neuropharmacology, La Jolla, California 92037.
Opioid peptides, and especially the dynorphins, have been localized to
several circuits in the CA3 hippocampal region, yet electrophysiological
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 pyramidal neurons
using single-electrode voltage-clamp recording in a slice preparation of
rat hippocampus. In most CA3 neurons, the voltage-dependent K+ current
known as the M-current (IM) was uniquely sensitive to the opioid peptides,
with the direction of response dependent upon the opiate type and
concentration. Thus, an opiate selective for kappa receptors, U-50,488H,
significantly augmented IM. The kappa-selective agonists dynorphin A and
dynorphin B, which exist in mossy fiber afferents to CA3 pyramidal neurons,
also markedly augmented IM at low concentrations (20-100 nM). By contrast,
dynorphin A at higher concentrations (1-1.5 microM) often reduced IM.
Similarly, several opiates [e.g., D-Ala2,D-Leu5-enkephalin: (DADL), [D-
Pen2,5]-enkephalin (DPDPE)] known to act on the delta receptor subtypes
reduced the M-current, with partial reversal of this effect by naloxone.
Neither the selective mu-receptor agonist [D-Ala2, NMe-Phe4,
Gly-ol]-enkephalin (DAMGO) nor the nonopioid fragment of dynorphin, des-
Tyr-dynorphin, consistently altered IM. These opiate effects on IM were
accompanied by changes in conductance and holding current consistent with
their respective effects on IM. Dynorphin A did not measurably affect the
Q-current, a conductance known to contribute to inward rectification in
hippocampal pyramidal neurons. The opiate effects on IM were not altered by
pretreatment with Cs+ (which blocks IQ) or Ca2+ channel blockers. The
opposing effects of the dynorphins (both A and B) and DADL on IM were
antagonized by naloxone (1-3 microM), and the dynorphin-induced
augmentations of IM were usually reversed by the kappa receptor antagonist
norbinaltorphimine. These results suggest that the opiates can have
opposing effects on the same voltage- dependent K+ channel type (the M
channel) in the rat CA3 pyramidal neuron, with the direction of the
response depending on which receptor subtype is activated. These data not
only help explain the mixed effects of opiates seen in other studies, but
also suggest a potential postsynaptic function for the endogenous opiates
contained in the CA3 mossy fibers.
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