title: Ketanserin potentiates morphine-induced antinociception mediated by kappa-receptor activation.
abstract: How can we treat patients with reduced morphine doses without loosing the pain killing effect or morphine antinociceptive effects (MAE)? To address this question, we hypothesized that serotonin (5-HT2) receptor antagonism could enhance MAE mediated by kappa-opioid receptors. We pretreated mice with ketanserin, a 5-HT2 receptor antagonist, and measured the morphine dose required to observe analgesia. The morphine dose effective in 50% of animals (ED(50)) was reduced from 4.7 to 1.3mg/kg, and the morphine dose effective in 100% of animals (ED(max)) from 13.7 to 2.5mg/kg. Ketanserin has a similar enhancer effect when morphine, which has a dual role via mu and kappa receptors, was substituted by the antinociceptive spiradoline, a selective κ-opioid agonist. At a morphine dose of 3.5mg/kg, 30% of the mice showed antinociceptive behaviour, rising to 100% when ketanserin was co-administered and then reduced to 20% in the presence of nor-binaltorphimine, a kappa-opioid receptor antagonist. Our data strongly suggests a serotonergic inhibition of the kappa-opioid component of MAE and the possibility that this serotonergic inhibition could be reversed through 5-HT2 receptor antagonism.
authors.affiliation: Alicante Clinical Trials Unit, Instituto de Bioingeniería, Miguel Hernández University, Campus de San Juan, Ctra, Alicante-Valencia, Km 87 Apdo 18, 03550 San Juan de Alicante, Alicante, Spain. peiro ana@gva.es
authors.forename: A M
authors.initials: AM
authors.lastname: Peiró
authors.forename: L
authors.initials: L
authors.lastname: Climent
authors.forename: P
authors.initials: P
authors.lastname: Zapater
authors.forename: A
authors.initials: A
authors.lastname: Horga
authors.forename: J F
authors.initials: JF
authors.lastname: Horga
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007650:Ketanserin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000494:pharmacology* / Q000627:therapeutic use; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D011224:Prazosin / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000700:Analgesics; D011759:Pyrrolidines; D018340:Receptors, Adrenergic, alpha-1; D017473:Receptors, Opioid, kappa; D044348:Receptors, Serotonin, 5-HT2; D012702:Serotonin Antagonists; C051844:norbinaltorphimine; D009271:Naltrexone; D009020:Morphine; D007650:Ketanserin; C051272:spiradoline; D011224:Prazosin