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Enhanced naloxone distribution to the brain by morphine pretreatment in mice
Abstract:
An increase in the disposition of naloxone to the mouse brain was observed for animals previously exposed to morphine. Compared to controls, mice receiving morphine sulfate (10 mg/kg, sc) 3 hr prior to naloxone had a 28% increase in naloxone concentration in brain (200 to 260 pmol of naloxone per g of brain) 10 min after 3H-naloxone-HCl (0.4 mg/kg, 11.0 micronCi/kg, sc) administration. Also, if similar morphine-pretreated mice received a second dose of morphine sulfate (1.0 mg/kg, sc) concurrent with 3H-naloxone-HCl, the morphine-induced enhancement of 3H-naloxone concentration in brain was unaltered. This drug-treatment protocol paralleled that used by others in pA2-analgesia assays to demonstrate sensitization to naloxone for morphine-pretreated animals. In prior (3 hr) morphine-treated animals, administration of 3H-naloxone-HCl (0.1 mg/kg, 33.3 micronCi/kg) iv resulted in an 11.0% increase in 3H-naloxone brain concentration after 1 min. Thus, the enhancement of naloxone brain concentration was independent of the route of naloxone administration. No enhancement of 3H-naloxone brain concentration could be seen 24 hr after morphine sulfate pretreatment (10 mg/kg, sc), a decline in the effect similar to that seen for morphine-induced sensitization to naloxone. Finally, when morphine pellet-implanted mice (75 mg of morphine base, 72 hr) were administered 3H-naloxone-HCl (0.4 mg/kg, 10.0 micronCi/kg, sc), only a 22.5% enhancement of 3H-naloxone concentration in brain was obtained, as opposed to a reported 8-fold increase in the potency of naloxone. Thus, although a number of similarities exist between the enhancement by morphine of naloxone concentration in brain and its sensitization to the antagonistic activity of naloxone, a quantitative correlation appears to be lacking between the two phenomena.
Insights
Morphine pretreatment increases naloxone brain concentration in mice, but this effect diminishes over time and does not directly correlate with naloxone
Area of Science:
- Pharmacology
- Neuroscience
- Toxicology
Background:
- Morphine, an opioid analgesic, can induce tolerance and dependence.
- Naloxone is an opioid antagonist used to reverse opioid effects.
- Previous exposure to morphine may alter the brain's response to naloxone.
Purpose of the Study:
- To investigate the effect of prior morphine exposure on naloxone brain disposition in mice.
- To explore the relationship between enhanced naloxone brain concentration and naloxone's antagonistic potency.
- To determine the time course and route independence of morphine-induced changes in naloxone brain levels.
Main Methods:
- Mice were pretreated with morphine sulfate via subcutaneous injection or implanted with morphine pellets.
- Radioactive 3H-naloxone hydrochloride was administered, and its brain concentration was measured at various time points.
- Comparisons were made between morphine-pretreated and control groups, and with established pA2-analgesia assay data.
Main Results:
- Morphine pretreatment (3 hours prior) increased naloxone brain concentration by 28% after subcutaneous administration.
- This enhancement was independent of naloxone's route of administration (subcutaneous vs. intravenous).
- The effect diminished significantly by 24 hours post-pretreatment and showed a weaker correlation with chronic morphine exposure compared to acute pretreatment.
Conclusions:
- Acute morphine exposure enhances naloxone's entry into the mouse brain.
- The observed increase in brain naloxone concentration following morphine pretreatment shows similarities to, but does not quantitatively correlate with, naloxone's increased potency in analgesia assays.
- This suggests distinct mechanisms underlying the disposition of naloxone in the brain and its functional antagonism.