Comparison of (+)- and (-)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice

• Published in: The Journal of pharmacology and experimental therapeutics 2016-08, Vol.358 (2), p.209-215
• Main Authors: Eriksen, Guro Søe, Andersen, Jannike Mørch, Boix, Fernando, Bergh, Marianne Skov-Skov, Vindenes, Vigdis, Rice, Kenner C, Huestis, Marilyn A, Mørland, Jørg
• Format: Article
• Language: English
• Subjects: Animals; Brain - cytology; Brain - drug effects; Brain - metabolism; Brain - physiology; Central Nervous System Stimulants - pharmacology; Heroin - antagonists & inhibitors; Heroin - pharmacology; Locomotion - drug effects; Male; Mice; Morphine - antagonists & inhibitors; Morphine - pharmacology; Morphine Derivatives - antagonists & inhibitors; Morphine Derivatives - pharmacology; Naloxone - blood; Naloxone - chemistry; Naloxone - pharmacokinetics; Naloxone - pharmacology; Neuropharmacology; Signal Transduction - drug effects; Stereoisomerism; Structure-Activity Relationship; Toll-Like Receptor 4 - metabolism
• ISSN: 1521-0103; 0022-3565; 1521-0103
• DOI: 10.1124/jpet.116.233544

Toll-like receptor 4 (TLR4) signaling is implied in opioid reinforcement, reward, and withdrawal. Here, we explored whether TLR4 signaling is involved in the acute psychomotor-stimulating effects of heroin, 6-acetylmorphine (6-AM), and morphine as well as whether there are differences between the three opioids regarding TLR4 signaling. To address this, we examined how pretreatment with (+)-naloxone, a TLR4 active but opioid receptor (OR) inactive antagonist, affected the acute increase in locomotor activity induced by heroin, 6-AM, or morphine in mice. We also assessed the effect of pretreatment with (-)-naloxone, a TLR4 and OR active antagonist, as well as the pharmacokinetic profiles of (+) and (-)-naloxone in the blood and brain. We found that (-)-naloxone reduced acute opioid-induced locomotor activity in a dose-dependent manner. By contrast, (+)-naloxone, administered in doses assumed to antagonize TLR4 but not ORs, did not affect acute locomotor activity induced by heroin, 6-AM, or morphine. Both naloxone isomers exhibited similar concentration versus time profiles in the blood and brain, but the brain concentrations of (-)-naloxone reached higher levels than those of (+)-naloxone. However, the discrepancies in their pharmacokinetic properties did not explain the marked difference between the two isomers' ability to affect opioid-induced locomotor activity. Our results underpin the importance of OR activation and do not indicate an apparent role of TLR4 signaling in acute opioid-induced psychomotor stimulation in mice. Furthermore, there were no marked differences between heroin, 6-AM, and morphine regarding involvement of OR or TLR4 signaling.