Peptide opioid antagonist separates peripheral and central opioid antitransit effects

Area of Science:

• Pharmacology
• Gastroenterology
• Neuroscience

Background:

• Opioid receptors are present both centrally and peripherally.
• The role of peripheral opioid receptors in gastrointestinal motility and opioid-induced side effects is not fully understood.

Purpose of the Study:

• To investigate if peripheral mu, delta, and kappa opioid receptors inhibit gastrointestinal transit.
• To determine if peripheral opioid receptors mediate morphine-induced constipation.
• To explore if constipation and analgesia can be dissociated based on different receptor sites.

Main Methods:

• Administered peripheral, selective opioid receptor agonists ([MePhe3,D-Pro4]morphiceptin for mu, [D-Pen2,D-Pen5]enkephalin for delta, dynorphin 1-9 for kappa) subcutaneously in mice.
• Assessed gastrointestinal transit rate.
• Used the hot-plate test to determine central nervous system penetration and analgesic effects.

Main Results:

• Peripherally administered [MePhe3,D-Pro4]morphiceptin significantly inhibited gastrointestinal transit at doses much lower than those causing analgesia.
• Central mu-opioid receptor blockade did not antagonize the peripheral anti-transit effects of [MePhe3,D-Pro4]morphiceptin.
• Evidence suggests peripheral mu-opioid receptors mediate gastrointestinal transit inhibition independently of central effects.

Conclusions:

• Peripheral mu-opioid receptors can inhibit gastrointestinal transit.
• Constipation induced by peripheral opioid receptor activation is separable from central analgesia.
• Peripheral opioid receptors play a significant role in gastrointestinal motility.