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Updated: May 20, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
The opioid placebo analgesia is mediated exclusively through μ-opioid receptor in rat
Rui-Rui Zhang1, Wen-Cai Zhang, Jin-Yan Wang
1Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, PR China.
Abstract:
Placebo analgesia is one of the most robust and best-studied placebo effects. Recent researches suggest that placebo analgesia activated the μ-opioid receptor signalling in the human brain. However, whether other opioid receptors are involved in the placebo analgesia remains unclear. We have previously evoked placebo responses in mice (Guo et al. 2010, 2011) and these mice may serve as a model for investigating placebo analgesia. In the present study, we tried to explore the site of action and types of opioid receptors involved in placebo response. Male Sprague-Dawley rats were trained with 10 mg/kg morphine for 4 d to establish the placebo analgesia model. This placebo analgesia can be blocked by injection of 5 mg/kg dose naloxone or by microinjection with naloxone (1, 3 or 10 μg/rat) into rostral anterior cingulate cortex (rACC). Then, animals were tested after intra-rACC microinjection of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP, a selective μ-opioid receptor antagonist) or naltrindole (NTI, a highly selective δ-opioid receptor antagonist) or nor-binaltorphimine (nor-BNI, a highly selective κ-opioid receptor antagonist). Our results showed that CTOP, but not NTI or nor-BNI, could reduce the pain threshold in placebo analgesia rats. It may be concluded that rACC is the key brain region involved in placebo analgesia and the opioid placebo analgesia is mediated exclusively through μ-opioid receptor in rat.
Insights
Placebo analgesia in rats involves the rostral anterior cingulate cortex (rACC). This pain relief is mediated exclusively by the mu-opioid receptor, not delta or kappa opioid receptors.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Placebo analgesia is a well-documented phenomenon.
- Existing research implicates mu-opioid receptor signaling in human placebo analgesia.
- The involvement of other opioid receptors in placebo analgesia remains largely unexplored.
Purpose of the Study:
- To investigate the brain region responsible for placebo analgesia.
- To determine which types of opioid receptors mediate placebo analgesia.
- To establish and utilize a rat model for studying placebo analgesia.
Main Methods:
- Established a placebo analgesia model in male Sprague-Dawley rats using morphine training.
- Administered naloxone to block placebo analgesia, including via microinjection into the rostral anterior cingulate cortex (rACC).
- Tested the effects of selective opioid receptor antagonists (CTOP for μ, NTI for δ, nor-BNI for κ) microinjected into the rACC.
Main Results:
- Placebo analgesia in rats was blocked by naloxone, particularly when microinjected into the rACC.
- Microinjection of CTOP (a μ-opioid receptor antagonist) into the rACC reduced the pain threshold in placebo analgesia rats.
- NTI (δ-opioid receptor antagonist) and nor-BNI (κ-opioid receptor antagonist) did not affect placebo analgesia when administered into the rACC.
Conclusions:
- The rostral anterior cingulate cortex (rACC) is a critical brain region for placebo analgesia.
- Opioid-mediated placebo analgesia in rats is exclusively dependent on the μ-opioid receptor.
- These findings provide insights into the neurobiological mechanisms of placebo effects.
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