Comparison of (+)- and (-)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice.
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.
Department of Drug Abuse Research, Division for Forensic Sciences, Norwegian Institute of Public Health, Oslo, Norway (G.S.E., J.M.A., F.B., M.S.-S.B., V.V., J.M.); Institute of Clinical Medicine, University of Oslo, Oslo, Norway (V.V., J.M.); University of Maryland School of Medicine, Baltimore, Maryland (M.A.H.); and Section on Drug Design and Synthesis, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (K.C.R) guro.soe.eriksen@fhi.no.
Guro Søe
GS
Eriksen
Department of Drug Abuse Research, Division for Forensic Sciences, Norwegian Institute of Public Health, Oslo, Norway (G.S.E., J.M.A., F.B., M.S.-S.B., V.V., J.M.); Institute of Clinical Medicine, University of Oslo, Oslo, Norway (V.V., J.M.); University of Maryland School of Medicine, Baltimore, Maryland (M.A.H.); and Section on Drug Design and Synthesis, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (K.C.R).
Jannike Mørch
JM
Andersen
Department of Drug Abuse Research, Division for Forensic Sciences, Norwegian Institute of Public Health, Oslo, Norway (G.S.E., J.M.A., F.B., M.S.-S.B., V.V., J.M.); Institute of Clinical Medicine, University of Oslo, Oslo, Norway (V.V., J.M.); University of Maryland School of Medicine, Baltimore, Maryland (M.A.H.); and Section on Drug Design and Synthesis, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (K.C.R).
Fernando
F
Boix
Department of Drug Abuse Research, Division for Forensic Sciences, Norwegian Institute of Public Health, Oslo, Norway (G.S.E., J.M.A., F.B., M.S.-S.B., V.V., J.M.); Institute of Clinical Medicine, University of Oslo, Oslo, Norway (V.V., J.M.); University of Maryland School of Medicine, Baltimore, Maryland (M.A.H.); and Section on Drug Design and Synthesis, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (K.C.R).
Marianne Skov-Skov
MS
Bergh
Department of Drug Abuse Research, Division for Forensic Sciences, Norwegian Institute of Public Health, Oslo, Norway (G.S.E., J.M.A., F.B., M.S.-S.B., V.V., J.M.); Institute of Clinical Medicine, University of Oslo, Oslo, Norway (V.V., J.M.); University of Maryland School of Medicine, Baltimore, Maryland (M.A.H.); and Section on Drug Design and Synthesis, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (K.C.R).
Vigdis
V
Vindenes
Department of Drug Abuse Research, Division for Forensic Sciences, Norwegian Institute of Public Health, Oslo, Norway (G.S.E., J.M.A., F.B., M.S.-S.B., V.V., J.M.); Institute of Clinical Medicine, University of Oslo, Oslo, Norway (V.V., J.M.); University of Maryland School of Medicine, Baltimore, Maryland (M.A.H.); and Section on Drug Design and Synthesis, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (K.C.R).
Kenner C
KC
Rice
Department of Drug Abuse Research, Division for Forensic Sciences, Norwegian Institute of Public Health, Oslo, Norway (G.S.E., J.M.A., F.B., M.S.-S.B., V.V., J.M.); Institute of Clinical Medicine, University of Oslo, Oslo, Norway (V.V., J.M.); University of Maryland School of Medicine, Baltimore, Maryland (M.A.H.); and Section on Drug Design and Synthesis, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (K.C.R).
Marilyn A
MA
Huestis
Department of Drug Abuse Research, Division for Forensic Sciences, Norwegian Institute of Public Health, Oslo, Norway (G.S.E., J.M.A., F.B., M.S.-S.B., V.V., J.M.); Institute of Clinical Medicine, University of Oslo, Oslo, Norway (V.V., J.M.); University of Maryland School of Medicine, Baltimore, Maryland (M.A.H.); and Section on Drug Design and Synthesis, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (K.C.R).
Jørg
J
Mørland
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003932:Heroin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009270:Naloxone / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D000697:Central Nervous System Stimulants; D009022:Morphine Derivatives; D051197:Toll-Like Receptor 4; D009270:Naloxone; D003932:Heroin; D009020:Morphine; C026979:6-O-monoacetylmorphine