title: Effects of cholinesterase inhibitors and serotonin-1A receptor agonists on morphine-induced ventilatory depression and antinociception in rats.
abstract: 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.
authors: Laboratory of Neuropharmacology, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.
authors: Satoko
authors: S
authors: Kimura
authors: Yoshiaki
authors: Y
authors: Ohi
authors: Akira
authors: A
authors: Haji
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000698:Analgesia; D000818:Animals; D002065:Buspirone / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D007189:Indans / Q000494:pharmacology*; D008297:Male; D009020:Morphine; D010146:Pain / Q000188:drug therapy; D010830:Physostigmine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000188:drug therapy*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D058825:Serotonin 5-HT1 Receptor Agonists; D009020:Morphine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000077265:Donepezil; D010830:Physostigmine; D002065:Buspirone