Opioids induce constipation by prompting alpha-Synuclein hyperphosphorylation in the colonic myenteric plexus

Area of Science:

• Gastroenterology
• Neuroscience
• Pharmacology

Background:

• Opioid-induced constipation (OIC) is a common side effect of opioid therapy.
• Alpha-synuclein (α-Syn) is vital for neurotransmitter homeostasis but its role in OIC is unclear.

Purpose of the Study:

• To investigate the impact of α-Syn hyperphosphorylation on colonic dysmotility in an OIC rat model.
• To elucidate the molecular mechanisms linking opioid use to OIC.

Main Methods:

• Utilized a Sprague-Dawley rat model of OIC.
• Assessed α-Syn phosphorylation at Ser129 (pS129-α-Syn) in the colonic myenteric layer.
• Measured expression of synaptic proteins and neurotransmitter synthases.
• Investigated the role of GSK3β and μ-opioid receptors (MOR).

Main Results:

• pS129-α-Syn expression was significantly increased in OIC rats.
• Inhibition of pS129-α-Syn reversed colonic dysmotility and restored synaptic protein expression.
• Opioids downregulate GSK3β via MOR activation, increasing GSK3β activity and inducing pS129-α-Syn.
• The GSK3β/pS129-α-Syn axis mediates opioid effects on synaptic vesicle trafficking and neurotransmitter release.

Conclusions:

• OIC development is linked to α-Syn hyperphosphorylation in colonic myenteric neurons.
• Opioids induce OIC by inhibiting synaptic function and neurotransmitter release through the GSK3β/α-Syn pathway.