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Updated: Aug 30, 2026
Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Mu-opioid receptor mRNA regulation during morphine tolerance in the rat peripheral nervous system
Thomas Meuser1, Thorsten Giesecke, Anja Gabriel
1Departments of *Anesthesiology and †Neurophysiology, University of Cologne, Cologne, Germany, ‡Department of Anesthesiology, University of Halle Wittenberg, Halle, Germany, and the §Department of Anesthesia, University of California, San Francisco, CA.
Unlabelled:
In vivo data on opioid receptor mRNA regulation after agonist exposure in the peripheral nervous system are lacking. Therefore, we studied the impact of morphine treatment on the regulation of mu-opioid receptor mRNA during behavioral signs of tolerance in rat peripheral sensory ganglia. Nineteen rats were treated in 2 groups with either morphine (10 mg/kg subcutaneously) or saline over 4 days, and a subset of rats received naloxone on the fifth day followed by either morphine injection on the sixth day or death to obtain dorsal root ganglia for mRNA analysis. Animals were tested on the hot plate during treatment days. To assess the levels of mu-opioid receptor mRNA, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used with the co-amplification of the "housekeeping" gene cyclophilin as internal control. Morphine treatment over 4 days induced tolerance as reflected on the hot-plate test by a significant reduction of paw-withdrawal latency from 242% to 99% above baseline. Using RT-PCR we demonstrated a down-regulation of mu-opioid receptor mRNA by 62% after morphine exposure (P < 0.05). After acute withdrawal of morphine from the mu-receptor by naloxone, the mu-opioid receptor mRNA levels in the dorsal root ganglia were restored to control levels within 24 h and the paw-withdrawal latency also returned to 280% above control. These data suggest that the peripheral nervous system may be an important site of opioid tolerance development.
Implications:
The peripheral nervous system is a possible site of opioid receptor tolerance. We show the development of behavioral tolerance and mu-opioid receptor mRNA down-regulation in the dorsal root ganglia in rats after chronic morphine treatment. Both this mRNA down-regulation and behavioral tolerance reverse after 24 h of naloxone treatment.
Insights
Chronic morphine treatment leads to opioid tolerance in the peripheral nervous system. This involves mu-opioid receptor mRNA down-regulation in dorsal root ganglia, which reverses with naloxone.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Limited in vivo data exist on opioid receptor mRNA regulation in the peripheral nervous system following agonist exposure.
- Opioid tolerance is a significant clinical challenge, and its underlying mechanisms require further elucidation.
Purpose of the Study:
- To investigate the impact of morphine on mu-opioid receptor mRNA regulation in rat peripheral sensory ganglia.
- To determine if the peripheral nervous system contributes to the development of opioid tolerance.
Main Methods:
- Rats were administered morphine or saline subcutaneously for 4 days.
- Behavioral tolerance was assessed using the hot plate test.
- Mu-opioid receptor mRNA levels in dorsal root ganglia were quantified using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR).
Main Results:
- Chronic morphine treatment induced significant behavioral tolerance, evidenced by reduced paw-withdrawal latency.
- A 62% down-regulation of mu-opioid receptor mRNA was observed in dorsal root ganglia after morphine exposure (P < 0.05).
- Following naloxone administration, both mu-opioid receptor mRNA levels and behavioral tolerance returned to control levels within 24 hours.
Conclusions:
- The peripheral nervous system is a potential site for the development of opioid receptor tolerance.
- Chronic morphine treatment leads to down-regulation of mu-opioid receptor mRNA in dorsal root ganglia, contributing to behavioral tolerance.
- Reversal of both molecular and behavioral changes with naloxone highlights the plasticity of the peripheral nervous system in opioid tolerance.
