Effects of μ-opioid receptor modulation on the hippocampal network activity of sharp wave and ripples.

BACKGROUND AND PURPOSE Hippocampus-dependent memory involves the activity of sharp wave ripples (SWRs), which are thought to participate in the process of memory consolidation. The hippocampus contains high levels of endogenous opioids and of μ-opioid receptors (MORs). Here, we have assessed the role of MOR agonists in the modulation of SWRs. EXPERIMENTAL APPROACH Using recordings of extracellular potentials from the CA1 field of rat hippocampal slices, we examined the pharmacological actions of morphine, DAMGO and fentanyl on SWRs and on network excitability and paired-pulse inhibition. KEY RESULTS All three MOR agonists (1 nM-10 μM) significantly increased the amplitude of sharp waves and the occurrence of SWR sequences, but reduced the initiation of episodes of SWRs. Fentanyl was most potent in producing these effects and morphine the least. Interestingly, although SWRs were reduced by relatively high concentrations (≥100 nM) of all agonists, they were significantly enhanced by very low concentrations of morphine (5-10 nM). Morphine and DAMGO at moderate-to-high concentrations increased network excitability and reduced inhibition. Furthermore, DAMGO suppressed inhibition more readily than it increased excitation, whereas morphine suppressed inhibition only at high concentrations. These drug effects were reversed by the MOR antagonists naloxone and CTOP. CONCLUSIONS AND IMPLICATIONS We found that the SWRs were significantly modulated by three MOR agonists and that the SWRs were very sensitive to subtle changes in the excitation/inhibition balance induced by MOR agonists. Such modulation might underlie the effects of these agonists on hippocampus-dependent memory.