Abstract
Postoperative cognitive dysfunction (POCD), mainly characterized by short-term decline of learning and memory, occurs after operations under anesthesia. However, the underlying mechanisms are poorly understood. The μ-opioid receptors (MOR) are highly expressed in interneurons of hippocampus, and is believed to be critical for the dysfunction of synaptic plasticity between hippocampal neurons. Therefore, we investigated the effect of fentanyl, a strong agonist of MOR and often used for anesthesia and analgesia in clinical settings, on hippocampal synaptic plasticity in the Schaffer-collateral CA1 pathway during acute exposure and washout in vitro. Our results revealed that acute fentanyl exposure (0.01, 0.1, 1 μM) dose-dependently increased the field excitatory postsynaptic potentials (fEPSPs), which was prevented by pre-administration of picrotoxin (50 μM) or MOR antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (CTOP, 10 μM). While fentanyl exposure-increased fEPSPs amplitude was prevented by picrotoxin [an inhibitor of γ-aminobutyric acid receptor (GABAR)] treatment or fentanyl washout, pretreatment of picrotoxin failed to prevent the fentanyl-impaired long-term potentiation (LTP) of synaptic strength as well as the fentanyl-enhanced long-term depression (LTD). These results demonstrated that fentanyl acute exposure and washout increases hippocampal excitability in the Schaffer-collateral CA1 pathway, depending on disinhibiting interneurons after MOR activation. In addition, fentanyl acute exposure and washout modulated synaptic plasticity, but the inhibitory activation was not critical. Elucidating the detailed mechanisms for synaptic dysfunction after fentanyl exposure and washout may provide insights into POCD generation after fentanyl anesthesia.
Highlights
Produced and synthesized opioid receptor agonists are often used as anesthetics and analgesics in clinical settings
When fentanyl (1 μM) was exposed to picrotoxin (50 μM) pre-treated slices, there was no significant further facilitation of field excitatory postsynaptic potentials (fEPSPs) amplitude in the Schaffercollateral pathway (Figures 1B,D; p > 0.05 Pic/Fen-1 group vs. Pic/Vehicle group), and fentanyl washout did not change fEPSPs either. These results suggested that fentanyl exposure indirectly promoted excitatory neurotransmission in the CA1 via inhibiting interneuron GABAergic input
We report here that selective activation of MOR by in vitro fentanyl acute exposure and washout to hippocampal slices increased basic synaptic transmission in the Schaffer-collateral pathway, through its effect on disinhibition of GABAergic interneurons
Summary
Produced and synthesized opioid receptor agonists are often used as anesthetics and analgesics in clinical settings. Electrophysiological, immunohistochemical, and in situ hybridization experiments have demonstrated that the hippocampus expresses a high density of opioid receptors (Zieglgänsberger et al, 1979; Lupica et al, 1992; Drake and Milner, 2002; Stumm et al, 2004; Drake et al, 2007). Along with these studies, μ-opioid receptors (MOR) are selectively expressed on GABAergic interneurons within the CA1 region of the hippocampus (Drake and Milner, 1999; Stumm et al, 2004). While activation of opioid receptors in the hippocampus by acute and chronic opioid exposure have demonstrated modulation of hippocampal plasticity and memory (Yang et al, 2004; Jafari-Sabet and JannatDastjerdi, 2009), the role of acute MOR activation and washout in hippocampal synaptic plasticity of the Schaffer-collateral CA1 pathway remains elusive
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