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J Pharmacol Exp Ther. 2016 Aug;358(2):209-15. doi: 10.1124/jpet.116.233544. Epub 2016 Jun 8.

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

Author information

1
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.
2
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).

Abstract

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.

PMID:
27278234
PMCID:
PMC4959094
DOI:
10.1124/jpet.116.233544
[Indexed for MEDLINE]
Free PMC Article

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