Aminoglycoside antibiotics can cause neuromuscular block by inhibiting Ca2+ influx into motor nerve terminals. P/Q-type Ca2+ channels, which are formed by alpha 1A subunits, are mainly responsible for depolarization-dependent presynaptic Ca2+ entry in motor neurons. We therefore investigated the possibility that aminoglycosides function as P/Q-type channel blockers. They inhibited [125I]-omega-CTx-MVIIC binding to P/Q-type channels in guinea pig cerebellum membranes with nanomolar IC50 values (e.g., 8 nM for neomycin). Divalent cations decreased the apparent affinity of neomycin. Barium inward currents through alpha 1A subunits expressed in Xenopus oocytes were partially blocked by therapeutic concentrations of aminoglycosides. This explains that therapeutically relevant concentrations of these drugs decrease the reserve of neuromuscular transmission, which can lead to neuromuscular block. We conclude that micromolar concentrations of aminoglycosides block not only N-type but also P/Q-type channels in mammalian neurons.

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Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), significantly potentiates analgesia when administered in animals together with opioids. The aim of the present study was to investigate the effects of fluvoxamine on sufentanil antinociception and tolerance. Following animal care committee approval, the effects of continuous infusions of fluvoxamine and sufentanil were studied in behavioural tests (hot-plate test, tail-flick test, catalepsy test) in SpragueDawley rats with a jugular vein catheter. Saline was administered as a control. The time-effect curves for continuous intravenous sufentanil indicate dose-related antinociception and rapid development of tolerance in the hot-plate and tail-flick tests. Co-administration of fluvoxamine with continuous sufentanil enhances antinociception and attenuates development of tolerance, most clearly seen in the tail-flick test. Fluvoxamine alone and saline were not effective. No animal showed catalepsy. As a side effect we observed a marked loss of body weight. The IC50 values of sufentanil binding with and without fluvoxamine addition are 0.56-+0.17 nM and 0.3?0.15 nM, respectively, indicating no direct effect on the occupancy of sufentanil on the p-receptor by this serotonin reuptake inhibitor. In conclusion, we were able to show that the combination of an opioid with an SSRI at low doses improves analgesia and decreases development of tolerance in nociceptive tests in rats. The clinical implications of these promising results in an animal model, however, await further investigation.