Ventilatory depression is a serious side-effect of
opioid analgesics.
Naloxone, an antagonist of
opioid receptors, eliminates not only
ventilatory depression but also
analgesic effect of
opioids. Pharmacological dissociation of adverse reactions from the main action is important clinically and basically.
Cholinergic and serotonergic mechanisms are suggested to counteract the
opioid-induced ventilatory disturbances, but their influence on
analgesia is still controversial. The present study evaluated the effects of
cholinesterase inhibitors and serotonin-1A (5-HT1A) receptor agonists on
morphine (1.0mg/kg, i.v.)-induced
ventilatory depression and
analgesia in rats. In anesthetized animals, spontaneous ventilation and hind leg withdrawal reflexes against nociceptive thermal stimuli were measured simultaneously.
Physostigmine (0.1 and 0.2mg/kg, i.v.) and
donepezil (0.5 and 1.0mg/kg, i.v.) relieved the
morphine-induced
ventilatory depression and enhanced its antinociception. On the other hand, (±)-8-hydroxy-2-(di-n-propylamino)
tetralin (8-
OH-DPAT, 0.03 and 0.1mg/kg, i.v.) and
buspirone (0.1 and 0.3mg/kg, i.v.) did not influence antinociception of
morphine while they restored the decreased ventilation. In unanesthetized animals, hypercapnic ventilatory response was measured by using whole-body plethysmography.
Physostigmine (0.3mg/kg, i.p.),
donepezil (1.0mg/kg, i.p.),
8-OH-DPAT (0.3mg/kg, i.p.) and
buspirone (3.0mg/kg, i.p.) all recovered the
morphine (10mg/kg, i.p.)-induced depression of hypercapnic ventilatory response. The present study suggests that activation of
cholinergic or serotonergic (5-HT1A) mechanisms may be a useful therapeutic approach for
morphine-induced
ventilatory depression without loss of its
analgesic action.