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

Abstract

BACKGROUND AND PURPOSEHippocampus-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 m-opioid receptors (MORs). Here, we have assessed the role of MOR agonists in the modulation of SWRs. EXPERIMENTAL APPROACHUsing 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 RESULTSAll three MOR agonists (1 nM-10 mM) 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 (Ն100 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 IMPLICATIONSWe 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. AbbreviationsICI, intra-cluster interval; IEI, inter-event interval; IEpI, inter-episode interval; MOR, m-opioid receptor; PPI, paired-pulse inhibition; PS, population spike; SWR, sharp wave ripple BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2012 1146 British Journal of Pharmacology (2013) IntroductionEndogenous and clinically administered opioids act on many receptors (Waldhoer et al., 2004) and are involved in a wide variety of functions (Drolet et al., 2001) including hippocampus-dependent learning and memory (Wise, 1989;Meilandt et al., 2004;Bodnar, 2010;Kesner and Warthen, 2010;Dacher and Nugent, 2011). Nevertheless, the mechanisms by which opioids affect hippocampus-dependent memory appear to be highly complex and poorly understood.The critical involvement of the hippocampus in learning and memory (Eichenbaum, 2004;Squire et al., 2004) is underpinned by a number of different types of neuronal activity supporting distinct processes (Battaglia et al., 2011). For example, it is assumed that the encoding of new information that occurs during active behaviour is associated with q oscillation (Hasselmo, 2005) whereas memory consolidation takes place during inactivity (Alvarez and Squire, 1994;McGaugh, 2000). It is generally thought that memory consolidation entails the generation of irregular activity of sharp wave ripples...

Hippocampal sharp waves and ripples: Effects of aging and modulation by NMDA receptors and L-type Ca2+ channels

“…Hence, the increased amplitude of sharp waves in CA1 might result from an increase in the activity of the CA3 circuit induced by CPP. The same mechanism may also underlie the enhancing effect of CPP on the ripple oscillation given that increase in the ripple oscillation apparently requires a mild increase in principal cell activity (Csicsvari et al, 1999a, Giannopoulos and Papatheodoropoulos, 2013.…”

“…Furthermore, the ability of the local circuitry to generate sequences of SWRs may also reside on changes in the basal excitability of the neuronal network. The generation of sequences of SWR events is favored by moderately lowering GABAergic transmission (Papatheodoropoulos andKoniaris, 2011, Giannopoulos andPapatheodoropoulos, 2013). More specifically, the reduction in the activity of alpha5 subunitcontaining GABA A receptors facilitates the formation of relatively long sequences of SWRs containing four or more events .…”

“…Several lines of evidence suggest that aging is accompanied by alterations in the balance between excitation and inhibition in the hippocampal neuronal network (Oh et al, 2010). These alterations might significantly contribute to the impairment in the ripple oscillation in old animals, given that ripple generation requires an accurate balance between excitation and inhibition in the local circuitry (Giannopoulos and Papatheodoropoulos, 2013). Furthermore, the ability of the local circuitry to generate sequences of SWRs may also reside on changes in the basal excitability of the neuronal network.…”

Synergistic effect of spexin and progesterone on pain sensitivity attenuation in ovariectomized rats

“…In addition, intra‐CA1 microinjection of spexin decreased pain sensitivity in both intact and ovariectomized female rats . Hippocampal CA3 region contains a wide variety of receptors which all are known to be involved in pain modulation . Some of these include NMDA, GABA, 5‐Hydroxytryptophan (5‐HT), dopamine, acetylcholine (Ach) and galanin receptors .…”

“…23 Hippocampal CA3 region contains a wide variety of receptors which all are known to be involved in pain modulation. 24 Some of these include NMDA, GABA, 5-Hydroxytryptophan (5-HT), dopamine, acetylcholine (Ach) and galanin receptors. 25 The hippocampus receives abundant galaninergic input from the medial septum, locus, and hypothalamus.…”