In vitro morphine metabolism by rat microglia.
Anna Rita Togna1, Letizia Antonilli1, Melania Dovizio2
1Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Neuropharmacology
|August 31, 2013
Summary
Microglia in the brain can transform morphine into its metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). This suggests brain-derived morphine glucuronides contribute to levels found in cerebrospinal fluid.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Morphine metabolism primarily occurs in the liver, producing M3G and M6G.
- UDP-glucuronosyltransferases (UGTs) are present in the brain, suggesting potential for central morphine metabolism.
Purpose of the Study:
- To investigate the role of microglia in transforming morphine into M3G and M6G.
- To determine if microglia express functional UGTs capable of morphine glucuronidation.
Main Methods:
- Primary neonatal rat microglia cultures were incubated with varying morphine concentrations.
- Morphine, M3G, and M6G levels were quantified.
- mRNA and protein expression of UGT isozymes (UGT1A1, UGT1A6, UGT1A7, UGT2B1) were analyzed.
- Prostaglandin E2 and nitrite release were measured.
Main Results:
- Microglia produced M3G under basal conditions and expressed UGT1A1, UGT1A6, and UGT1A7.
- Exposure to exogenous morphine led to M6G synthesis, associated with UGT1A7 upregulation.
- Prolonged morphine exposure decreased UGT expression.
- Morphine did not affect PGE2 or nitrite release, indicating no generalized microglial activation.
Conclusions:
- Microglia can metabolize morphine into M3G and M6G.
- Brain-derived morphine glucuronides may contribute to cerebrospinal fluid levels.
- This reconciles the presence of hydrophilic morphine glucuronides within the brain.
