Related Experiment Video
Updated: Aug 19, 2026
Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Characterization of morphine-induced hyperalgesia in male and female rats
Joseph R Holtman1, Elzbieta P Wala
1Department of Anesthesiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0293, USA. jrjr@uky.edu
Abstract:
The pain enhancing (hyperalgesic) effect of morphine was characterized in relation to pain stimulus (thermal, mechanical), dose, mode of administration (acute, chronic), sex and mechanism. We found that a low (subanalgesic) dose of morphine enhanced the sensitivity to thermal and mechanical noxious stimuli in a dose- and sex-related manner. Morphine hyperalgesia was inversely related to dose (0.002-0.2mg/kg) and was more pronounced in female than male rats. The N-methyl-d-aspartate receptor antagonist, ketamine, antagonized morphine hyperalgesia. Tolerance developed to hyperalgesia following repeated (chronic) dosing with low dose morphine. Several additional findings were noted in rats tolerant to morphine-induced hyperalgesia. The efficacy of an analgesic dose of morphine was increased (female rats). Sex-related differences in morphine's analgesic action (male>female) were attenuated. Development of tolerance to the analgesic effect of morphine was delayed. The present findings may have an implication for the use of mu opioids in the clinical setting.
Insights
Low-dose morphine can paradoxically increase pain sensitivity (hyperalgesia) in a dose- and sex-dependent manner. Tolerance to this effect can develop, altering morphine
Area of Science:
- Pharmacology
- Neuroscience
- Pain Research
Background:
- Morphine, a widely used opioid analgesic, can exhibit complex dose-dependent effects on pain perception.
- Understanding the mechanisms underlying morphine's hyperalgesic effects is crucial for optimizing pain management strategies.
Purpose of the Study:
- To characterize the pain-enhancing (hyperalgesic) effects of morphine.
- To investigate the influence of dose, sex, and administration mode on morphine-induced hyperalgesia.
- To explore the role of N-methyl-d-aspartate (NMDA) receptors and the development of tolerance.
Main Methods:
- Utilized thermal and mechanical pain stimuli in a rat model.
- Administered varying doses of morphine via acute and chronic routes.
- Investigated the effects of the NMDA receptor antagonist ketamine.
- Assessed changes in pain sensitivity and analgesic efficacy following chronic morphine administration.
Main Results:
- Low-dose morphine (subanalgesic) induced hyperalgesia in a dose- and sex-related manner, being more pronounced in female rats.
- Morphine-induced hyperalgesia was inversely related to dose and antagonized by ketamine.
- Tolerance to morphine hyperalgesia developed with chronic low-dose administration.
- In tolerant rats, morphine analgesic efficacy increased in females, sex differences in analgesia were attenuated, and tolerance to analgesic effects was delayed.
Conclusions:
- Morphine can exert paradoxical pain-enhancing effects, particularly at low doses, with significant sex-based differences.
- NMDA receptor antagonism and tolerance development modulate these hyperalgesic and analgesic effects.
- Findings suggest clinical implications for optimizing mu-opioid therapy and managing potential hyperalgesia.
