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

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


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • 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*
  • Signal Transduction / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship
  • Toll-Like Receptor 4 / metabolism


  • Central Nervous System Stimulants
  • Morphine Derivatives
  • Toll-Like Receptor 4
  • Naloxone
  • Heroin
  • Morphine
  • 6-O-monoacetylmorphine