Effects of direct- and indirect-acting serotonin receptor agonists on the antinociceptive and discriminative stimulus effects of morphine in rhesus monkeys.

Abstract

Serotonergic (5-HT) systems modulate pain, and drugs acting on 5-HT systems are used with opioids to treat pain. This study examined the effects of 5-HT receptor agonists on the antinociceptive and discriminative stimulus effects of morphine in monkeys. Morphine increased tail-withdrawal latency in a dose-related manner; 5-HT receptor agonists alone increased tail-withdrawal latency at 50 °C but not 55 °C water. The antinociceptive effects of morphine occurred with smaller doses when monkeys received an indirect-acting (fenfluramine) or direct acting (8-OH-DPAT, F13714, buspirone, quipazine, DOM, and 2C-T-7) agonist. The role of 5-HT receptor subtypes in these interactions was confirmed with selective 5-HT(1A) (WAY100635) and 5-HT(2A) (MDL100907) receptor antagonists. None of the 5-HT drugs had morphine-like discriminative stimulus effects; however, fenfluramine and 5-HT(2A) receptor agonists attenuated the discriminative stimulus effects of morphine and this attenuation was prevented by MDL100907. The 5-HT(1A) receptor agonists did not alter the discriminative stimulus effects of morphine. Thus, 5-HT receptor agonists increase the potency of morphine in an assay of antinociception, even under conditions where 5-HT agonists are themselves without effect (ie, 55 °C water), without increasing (and in some cases decreasing) the potency of morphine in a drug discrimination assay. Whereas 5-HT(2A) receptor agonists increase the potency of morphine for antinociception at doses that have no effect on the rate of operant responding, 5-HT(1A) receptor agonists increase the potency of morphine only at doses that eliminate operant responding. These data suggest that drugs acting selectively on 5-HT receptor subtypes could help to improve the use of opioids for treating pain.

• Authors: Jun-Xu Li, Wouter Koek, Kenner C Rice, Charles P France
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 36 Issue 5 Pg. 940-9 (Apr 2011) ISSN: 1740-634X [Electronic] England
• PMID: 21209613 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Drug Combinations
• Fluorobenzenes
• Narcotics
• Piperidines
• Serotonin Antagonists
• Serotonin Receptor Agonists
• Serotonin Uptake Inhibitors
• Fenfluramine
• Morphine
• volinanserin

Topics

• Animals
• Behavior, Animal (drug effects)
• Conditioning, Operant (drug effects)
• Discrimination, Psychological (drug effects, physiology)
• Dose-Response Relationship, Drug
• Drug Combinations
• Drug Interactions
• Fenfluramine (pharmacology)
• Fluorobenzenes (pharmacology)
• Hot Temperature (adverse effects)
• Humans
• Hyperalgesia (drug therapy)
• Macaca mulatta
• Male
• Morphine (therapeutic use)
• Narcotics (therapeutic use)
• Pain Threshold (drug effects)
• Piperidines (pharmacology)
• Reaction Time (drug effects)
• Serotonin Antagonists (pharmacology)
• Serotonin Receptor Agonists (pharmacology)
• Selective Serotonin Reuptake Inhibitors (pharmacology)