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Chronopharmacological study on morphine-induced increase in ambulatory activity in mice and methamphetamine
Abstract:
Effect of morphine (5 and 10 mg/kg sc) on ambulatory activity was investigated at different times of day (administration at 3:00, 7:00, 11:00, 15:00, 19:00 and 23:00) in mice housed under a normal light-dark condition (light period; 6:00-18:00). Morphine increased the ambulatory activity in a dose-dependent manner when it was administered to the drug-naive mice. There was no clear circadian variation in the increased ambulatory activity. The repeated administration of morphine (10 mg/kg) at intervals of 7 days produced an augmentation in the sensitivity to the ambulation-increasing effect of morphine independently of the times of day, and the mean overall ambulatory activity counts during 3 hr observation period in the 5th administration were about 2 times as high as corresponding those in the 1st administration. The mice experienced the repeated administration of morphine (10 mg/kg) for 5 times during the mid-late light, and mid dark (administration at 11:00, 15:00 and 23:00) showed an increased sensitivity to the ambulation-increasing effect of methamphetamine (1 mg/kg sc). However, the circadian variation in sensitivity to methamphetamine, which was highest and lowest during the dark and light periods, respectively, was still maintained even in the morphine-experienced mice.
Insights
Repeated morphine doses increase ambulatory activity and sensitivity to both morphine and methamphetamine. This heightened sensitivity persists regardless of administration time, though circadian rhythms influence methamphetamine response.
Area of Science:
- Pharmacology
- Neuroscience
- Chronobiology
Background:
- Opioid analgesics like morphine can influence motor activity.
- Circadian rhythms, the body's internal 24-hour clock, affect drug responses.
- Understanding how repeated drug exposure interacts with circadian rhythms is crucial for therapeutic applications.
Purpose of the Study:
- To investigate the effect of morphine on ambulatory activity at different times of day.
- To examine the impact of repeated morphine administration on sensitivity to both morphine and methamphetamine.
- To determine if circadian variations influence these effects.
Main Methods:
- Mice were administered morphine (5 and 10 mg/kg) at various times over a 24-hour light-dark cycle.
- Ambulatory activity was measured to assess drug effects.
- Repeated morphine administration (10 mg/kg) was conducted over several days.
- Sensitivity to methamphetamine was tested in morphine-experienced mice.
Main Results:
- Morphine dose-dependently increased ambulatory activity in drug-naive mice.
- Repeated morphine administration led to a two-fold increase in sensitivity to its own effects, independent of administration time.
- Morphine-experienced mice showed increased sensitivity to methamphetamine.
- Circadian variations in methamphetamine sensitivity were maintained, being highest during the dark phase and lowest during the light phase.
Conclusions:
- Repeated morphine exposure augments locomotor activity and tolerance development.
- While morphine tolerance is time-independent, subsequent responses to other stimulants like methamphetamine retain circadian rhythmicity.
- These findings highlight the complex interplay between drug exposure history, circadian factors, and stimulant-induced behaviors.