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Updated: Oct 4, 2025

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Chronic Morphine Induces IL-18 in Ileum Myenteric Plexus Neurons Through Mu-opioid Receptor Activation in Cholinergic

Karan H Muchhala1, Eda Koseli1, Aravind R Gade1

  • 1Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, 1112 E. Clay Street, Richmond, VA, 23298, USA.

Journal of Neuroimmune Pharmacology : the Official Journal of the Society on Neuroimmune Pharmacology
|February 2, 2022
PubMed

Insights

Chronic morphine exposure increases Interleukin-18 (IL-18) in mouse ileum neurons by activating mu-opioid receptors (MORs). This finding sheds light on how morphine affects the gut-brain axis and gut barrier function.

Area of Science:

  • Neurogastroenterology
  • Pharmacology
  • Microbiome Research

Background:

  • The gut epithelium maintains symbiosis with microbiota, but chronic morphine compromises this barrier, causing dysbiosis.
  • Morphine-induced dysbiosis is linked to antinociceptive tolerance and reward, suggesting a gut-brain axis role.
  • The mechanisms behind morphine's effects on the gut microbiome are unclear, though Interleukin-18 (IL-18) from enteric neurons impacts gut barrier function.

Purpose of the Study:

  • To investigate the effect of chronic morphine exposure on IL-18 expression in the mouse ileum.
  • To characterize morphine's impact on the excitability of myenteric neurons expressing mu-opioid receptors (MORs).

Main Methods:

  • In vivo chronic morphine administration in mice.
  • Immunohistochemistry to detect IL-18 expression in the ileum myenteric plexus.
  • Electrophysiology to assess the excitability of cholinergic and vasoactive intestinal peptide (VIP)-expressing myenteric neurons.

Main Results:

  • Chronic morphine exposure induced IL-18 expression in the ileum myenteric plexus, an effect attenuated by naloxone.
  • VIP neurons exhibited higher excitability than cholinergic neurons.
  • MORs were predominantly found on cholinergic neurons, with a subset of VIP neurons also expressing MORs and responding to morphine.

Conclusions:

  • Morphine activates MORs in a subset of ileum myenteric plexus neurons (cholinergic and VIP) to increase IL-18 expression.
  • Understanding MOR-expressing enteric neurons is crucial for elucidating how morphine disrupts the gut barrier.
Keywords:
Chronic morphineEnteric neuronsGut epithelial barrierInterleukin-18 (IL-18)Mu-opioid receptorNeurochemical coding

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