Abstract
Analgesics and sedative hypnotics in clinical use often give rise to significant side effects, particularly respiratory depression. For emergency use, specific antagonists are currently administered to counteract respiratory depression. However, antagonists are often short-lasting and eliminate drug generated analgesia. To resolve this issue, novel positive AMPA modulators, LCX001, was tested to alleviate respiratory depression triggered by different drugs. The acetic acid writhing and hot-plate test were conducted to evaluate analgesic effect of LCX001. Binding assay, whole-cell recording, live cell imaging, and Ca2+ imaging were used to clarify mechanism and impact of LCX001 on respiratory protection. Results showed that LCX001 effectively rescued and prevented opioid (fentanyl and TH-030418), propofol, and pentobarbital-induced respiratory depression by strengthening respiratory frequency and minute ventilation. The acetic acid writhing test and hot-plate test revealed potent anti-nociceptive efficacy of LCX001, in contrast to other typical ampakines that did not affect analgesia. Furthermore, LCX001 potentiated [3H]AMPA and L-glutamate binding affinity to AMPA receptors, and facilitated glutamate-evoked inward currents in HEK293 cells stably expressing GluA2(R). LCX001 had a typical positive modulatory impact on AMPAR-mediated function. Importantly, application of LCX001 generated a significant increase in GluA2(R) surface expression, and restrained opioid-induced abnormal intracellular Ca2+ load, which might participate in breathing modulation. Our study improves therapeutic interventions for the treatment of drug induced respiratory depression, and increases understanding of potential mechanism of AMPA receptor modulators.
Highlights
Analgesics and sedative drugs are irreplaceable for clinical treatment, and administered for the induction and maintenance of anesthesia (Searle and Sahab, 1993; Kimura and Haji, 2014)
LCX001 in doses of 1.5, 3, 6, and 12 mg/kg inhibited acetic acid-induced writhing by 30.76 ± 12.75%, 41.43 ± 11.32%, 85.35 ± 9.53%, and 94.78 ± 2.74%, respectively. These results indicated that LCX001 had a significant antinociceptive effect at 1.5 mg/kg or higher doses (Figure 2A, ∗P < 0.05), and a 10 mg/kg dose of LCX001, similar to morphine at 2.5 mg/kg, produced a marked analgesic effect on writhing behaviors induced by acetic acid
The treatment of LCX001 (12 mg/kg) exerted no impact on the analgesic effect of morphine (Figures 2A,B, vehicle+morphine vs. LCX001+morphine, P > 0.05). These results demonstrated that LCX001 at doses of 6 mg/kg or higher produced anti-nociceptive behavior in both acetic acid writhing and hot-plate tests
Summary
Analgesics and sedative drugs are irreplaceable for clinical treatment, and administered for the induction and maintenance of anesthesia (Searle and Sahab, 1993; Kimura and Haji, 2014). Analgesic and sedative drug-induced respiratory depression is still an unresolved and significant problem in clinical treatment and it can be a leading cause of death (Dahan et al, 2010). Due to the non-specificity of receptor activation, respiratory depression is commonly experienced with analgesic and sedative drug use (Dai et al, 2017). Opioids are frequently overcommitted and used in combination with other sedative substances (alcohol, zolpidem, etc.) by abusers. These scenarios enormously increase the risk of death triggered by respiratory depression (Hasegawa et al, 2014; Fala and Welz, 2015). Antagonists (naloxone, flumazenil etc) are effectively administered to rescue varying degrees of suppressed respiration. Arrhythmia and convulsion can be produced by flumazenil at high doses (Roncari et al, 1986; Amrein et al, 1987)
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