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Updated: Oct 25, 2025

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Repeated Endomorphin Analogue MEL-0614 Reduces Tolerance and Improves Chronic Postoperative Pain without Modulating

Shuang Wei1, Chao-Zhen-Yi Han1, Jing Wang1

  • 1Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China.

ACS Chemical Neuroscience
|August 5, 2021
PubMed

Insights

MEL-0614, a novel endomorphin analogue, offers superior pain relief for chronic postoperative pain (CPSP) compared to morphine. It demonstrates less tolerance and prevents morphine-induced tolerance, presenting a promising alternative for long-term pain management.

Area of Science:

  • Pharmacology
  • Pain Management
  • Neuroscience

Background:

  • Chronic postoperative pain (CPSP) presents significant clinical challenges.
  • Current treatments like chronic morphine are limited by side effects and tolerance.
  • Novel analgesics are needed for effective and safe long-term pain management.

Purpose of the Study:

  • To compare the antinociceptive effects and tolerance development of MEL-0614 and morphine in a murine model of CPSP.
  • To investigate the underlying mechanisms of action and potential for cross-tolerance.
  • To evaluate MEL-0614's impact on pain recovery and neuroinflammation.

Main Methods:

  • Utilized a skin/muscle incision and retraction (SMIR) mice model to induce CPSP.
  • Administered MEL-0614 and morphine intrathecally (i.t.) to assess dose-dependent analgesia.
  • Evaluated long-term treatment effects on antinociceptive tolerance and pain recovery.
  • Assessed microglial activation and inflammatory markers (Iba1, P2X7R) via molecular analysis.

Main Results:

  • MEL-0614 demonstrated dose-dependent analgesia superior to morphine in the SMIR model.
  • Long-term MEL-0614 treatment did not induce tolerance, unlike morphine.
  • MEL-0614 prevented or inhibited morphine-induced tolerance through co-administration.
  • MEL-0614 accelerated pain recovery and reduced neuroinflammation (microglia, P2X7R, inflammatory factors), while morphine exacerbated pain and increased inflammation.

Conclusions:

  • MEL-0614 exhibits superior analgesic efficacy and reduced tolerance compared to morphine for CPSP.
  • MEL-0614 mitigates neuroinflammation and accelerates recovery, unlike morphine.
  • MEL-0614 represents a promising therapeutic candidate for long-term management of chronic postoperative pain.
Keywords:
Chronic postoperative painMicrogliaOpioid peptideP2X receptor 7Tolerance

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