Ketanserin potentiates morphine-induced antinociception mediated by kappa-receptor activation

• Published in: Pharmacological research Vol. 64; no. 1; pp. 80 - 84
• Main Authors: Peiró, A.M., Climent, L., Zapater, P., Horga, A., Horga, J.F.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-07-2011
• Subjects: Adrenergic alpha-1 Receptor Antagonists - pharmacology; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Antinociception; Dose-Response Relationship, Drug; Drug Synergism; ED 50; Kappa opioid receptor; Ketanserin; Ketanserin - pharmacology; Ketanserin - therapeutic use; Male; Mice; Mice, Inbred Strains; Morphine; Morphine - pharmacology; Morphine - therapeutic use; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Pain - drug therapy; Pain Measurement - methods; Pain Threshold - drug effects; Prazosin - pharmacology; Pyrrolidines - pharmacology; Receptors, Adrenergic, alpha-1 - metabolism; Receptors, Opioid, kappa - agonists; Receptors, Opioid, kappa - antagonists & inhibitors; Receptors, Opioid, kappa - metabolism; Receptors, Serotonin, 5-HT2 - metabolism; Serotonin Antagonists - pharmacology; Spiradoline; Antinociception; Morphine; Spiradoline; Kappa opioid receptor; ED 50; Ketanserin
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2011.02.009

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 1.3
mg/kg, and the morphine dose effective in 100% of animals (ED
max) from 13.7 to 2.5
mg/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 3.5
mg/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.