Selective 5-HT1A-R-agonist Repinotan Prevents Remifentanil-induced Ventilatory Depression and Prolongs Antinociception

Background: 5-HT1A-R-agonist repinotan was shown to counteract a morphine-induced ventilatory depression but had pronociceptive effects at small doses (0.2 mu g/kg). It remained to be clarified (1) whether a moderate dose of repinotan, sufficient to stimulate spontaneous breathing, impairs antinociception if plasma concentration decreases over time, and if (2) moderate doses prevent ventilatory depression if given before the opioid. Methods: A dose-response curve of the repinotan effects on spontaneous minute ventilation during continuous remifentanil infusion in anesthetized rats was established to identify moderate doses: (1) tail-flick reflex latencies to assess nociception were recorded until 60 min after cessation of a continuous remifentanil infusion with or without a concomitant moderate repinotan dose (10 mu g/kg), and (2) remifentanil boluses (2.5 mu g/kg) were given after repinotan (10 and 20 mu g/kg). Results: (1) Remifentanil-induced antinociception lasted only 5 min after infusion was stopped (tail-flick reflex latencies; median [interquartile range], 97 [54-100]% of maximum possible effect; P = 0.034), but was extended by repinotan (10 mu g/kg) to 30 min (tail-flick reflex latencies, 100 [75-100]% of maximum possible effect; P = 0.031). Repinotan (10 mu g/kg) alone did not have any significant antino-ciceptive effect. (2) The ventilatory depression by remifentanil boluses (2.5 mu g/kg; minute ventilation, -65 [-81to -56]%; P = 0.031, n = 5) was blunted by repinotan (20 mu g/kg; minute ventilation, -24 [-53 to 13]%; P = 0.313, compared with the pretreatment level). Conclusions: Repinotan prevented remifentanil-induced ventilatory depression in spontaneously breathing, anesthetized rats. Although repinotan did not depress nociception itself, it prolonged the profound antinociception after discontinuation of remifentanil infusion.