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Updated: Aug 25, 2026
Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Behavioral and electrophysiological evidence for tolerance to continuous morphine administration into the
D A Lane1, V Tortorici, M M Morgan
1Washington State University Vancouver, 14204 Northeast Salmon Creek Avenue, Vancouver, WA 98686, USA.
Abstract:
Repeated microinjections of morphine into the ventrolateral periaqueductal gray (vPAG) produce tolerance to the antinociceptive effect of morphine [Behav Neurosci 113 (1999) 833]. These results may be a direct effect of morphine on cells within the vPAG or be caused by cues linked to the microinjection procedure (i.e. associative tolerance). The objective of this paper was to determine whether continuous administration of morphine into the vPAG (i.e. no cues) would produce tolerance. Tolerance was assessed by measuring changes in behavior and changes in the activity of neurons in the rostral ventromedial medulla (RVM), the primary output target of the PAG. Rats were implanted with an osmotic minipump that released morphine (2.5 or 5 microg/h) or saline into the vPAG continuously. Continuous administration of morphine produced an increase in hotplate latency when measured 6 h after initiation of treatment. Tolerance to this antinociception was evident within 24 h. After 3 days, rats were anesthetized and the activity of RVM neurons was assessed. Although acute morphine administration into the RVM inhibits the activity of RVM on-cells and enhances the activity of off-cells, these neurons appeared normal following 3 days of continuous morphine administration. Systemic naloxone administration produced hyperalgesia that was associated with a marked increase in on-cell activity and a complete cessation of off-cell activity. The loss of morphine inhibition of nociception, measured behaviorally and electrophysiologically, demonstrates that tolerance is caused by a direct action of morphine on vPAG neurons.
Insights
Continuous morphine administration into the ventrolateral periaqueductal gray (vPAG) causes tolerance to its pain-relieving effects. This tolerance results from direct actions of morphine on vPAG neurons, not procedural cues.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Repeated morphine microinjections into the ventrolateral periaqueductal gray (vPAG) induce tolerance to antinociception.
- This tolerance could stem from direct drug effects or associative learning linked to the injection procedure.
Purpose of the Study:
- To investigate if continuous morphine administration into the vPAG, without procedural cues, leads to tolerance.
- To differentiate between direct pharmacological tolerance and associative tolerance.
Main Methods:
- Rats received continuous morphine (2.5 or 5 microg/h) or saline via osmotic minipumps into the vPAG.
- Tolerance was assessed behaviorally (hotplate test) and electrophysiologically by monitoring rostral ventromedial medulla (RVM) neuronal activity.
Main Results:
- Continuous vPAG morphine administration induced antinociception, with tolerance developing within 24 hours.
- After 3 days, RVM on- and off-cell activity remained normal, but systemic naloxone caused hyperalgesia, indicating functional opioid withdrawal.
- Behavioral and electrophysiological data confirmed tolerance due to direct morphine action on vPAG neurons.
Conclusions:
- Continuous morphine delivery to the vPAG causes tolerance independent of injection-associated cues.
- Tolerance to morphine's antinociceptive effects is mediated by direct actions on vPAG neurons.
