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Updated: Aug 15, 2026
Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Intermittent dosing prolongs tolerance to the antinociceptive effect of morphine microinjection into the
Michael M Morgan1, Bradley W Tierney, Susan L Ingram
1Department of Psychology, Washington State University Vancouver, 98686, USA. morgan@vancouver.wsu.edu
Abstract:
Tolerance to the antinociceptive effect of microinjecting morphine into the ventrolateral periaqueductal gray (vPAG) develops with repeated administration. The objective of the present experiment was to determine whether the magnitude and duration of tolerance differ depending on the interval between injections. Rats were injected with morphine or saline into the vPAG either once daily for 4 days or twice daily for 2 days. All rats were injected with morphine into the vPAG for the fifth injection to determine whether tolerance had developed. Morphine microinjection produced tolerance in both morphine-pretreated groups regardless of inter-dose interval. One and two weeks later, microinjection of morphine produced an increase in hot plate latency in all groups except rats pretreated with daily morphine microinjections. That is, tolerance was evident 2 weeks following the induction of tolerance produced by daily, but not twice daily injections of morphine. Although a long inter-dose interval has been shown to prolong the duration of tolerance after systemic morphine administration, this is the first report showing a similar effect with direct administration of morphine into the brain. Given that associative learning underlies prolonged tolerance with systemic morphine administration, the present data suggest that associative mechanisms of tolerance are also engaged when morphine administration is restricted to the PAG.
Insights
Repeated morphine injections into the brain
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Tolerance to morphine's pain-relieving effects can develop with repeated use.
- The ventrolateral periaqueductal gray (vPAG) is a key brain region for morphine's antinociceptive action.
- Understanding tolerance mechanisms is crucial for effective pain management.
Purpose of the Study:
- To investigate if the interval between morphine injections affects tolerance development and duration.
- To compare tolerance magnitude and duration following different dosing schedules of direct vPAG morphine administration.
Main Methods:
- Rats received microinjections of morphine or saline into the vPAG.
- Two dosing schedules were used: once daily for 4 days or twice daily for 2 days.
- Antinociceptive tolerance was assessed by measuring hot plate latency after a challenge morphine injection at later time points.
Main Results:
- Morphine microinjection induced tolerance in both groups, irrespective of the inter-dose interval.
- Tolerance persisted for 2 weeks in rats receiving daily injections, but not in those receiving twice-daily injections.
- This suggests that longer intervals between direct brain morphine administration prolong tolerance duration.
Conclusions:
- Direct morphine administration into the vPAG leads to tolerance.
- The duration of morphine tolerance is dependent on the inter-dose interval, with longer intervals prolonging tolerance.
- Associative learning mechanisms may contribute to prolonged tolerance even when morphine is administered directly into the brain's pain-modulating circuits.
