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Involvement of the Peripheral μ-Opioid Receptor in Tramadol-Induced Constipation in Rodents
Kana Yasufuku1, Katsumi Koike1, Mika Kobayashi2
1Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd.
Biological & Pharmaceutical Bulletin
|November 1, 2021
Summary
Tramadol causes constipation by activating peripheral μ-opioid receptors (MOR). Blocking these receptors with naldemedine or using MOR-knockout mice reversed this effect, clarifying tramadol
Area of Science:
- Pharmacology
- Gastroenterology
- Pain Management
Background:
- Tramadol, a weak opioid analgesic, acts on μ-opioid receptors (MOR) and non-opioid targets.
- Opioid-induced constipation is a prevalent side effect, particularly in patients with chronic pain.
- The specific role of MOR in tramadol-induced constipation remains incompletely understood.
Purpose of the Study:
- To investigate the involvement of peripheral MOR in tramadol-induced constipation.
- To elucidate the mechanism underlying tramadol's gastrointestinal side effects.
Main Methods:
- Utilized a small intestinal transit model in rats and mice.
- Administered tramadol orally and subcutaneously.
- Employed naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice for mechanistic studies.
Main Results:
- Tramadol dose-dependently inhibited small intestinal transit in rats.
- Naldemedine effectively blocked tramadol-induced inhibition of intestinal transit in a dose-dependent manner.
- Tramadol failed to inhibit intestinal transit in MOR-knockout mice, unlike in wild-type mice.
Conclusions:
- Peripheral MOR plays a significant role in mediating tramadol-induced constipation.
- Targeting peripheral MOR may offer a strategy to manage tramadol-related gastrointestinal side effects.
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