Selective 5-HT(1A)-R-agonist repinotan prevents remifentanil-induced ventilatory depression and prolongs antinociception.

Abstract

5-HT(1A)-R-agonist repinotan was shown to counteract a morphine-induced ventilatory depression but had pronociceptive effects at small doses (0.2 μg/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. 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 μg/kg), and (2) remifentanil boluses (2.5 μg/kg) were given after repinotan (10 and 20 μg/kg). (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 μg/kg) to 30 min (tail-flick reflex latencies, 100 [75-100]% of maximum possible effect; P = 0.031). Repinotan (10 μg/kg) alone did not have any significant antinociceptive effect. (2) The ventilatory depression by remifentanil boluses (2.5 μg/kg; minute ventilation, -65 [-81 to -56]%; P = 0.031, n = 5) was blunted by repinotan (20 μg/kg; minute ventilation, -24 [-53 to 13]%; P = 0.313, compared with the pretreatment level). 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.