ABSTRACT
In rodents, morphine analgesia is influenced by sex. However, conflicting results exist regarding the interaction between sex and morphine analgesic tolerance. Morphine is metabolized in the liver and brain into morphine-3-glucuronide (M3G). Sex differences in morphine metabolism and differential metabolic adaptations during tolerance development might explain the behavioral discrepancies. The present article investigates the differences in peripheral and central morphine metabolism after acute and chronic morphine treatment in male and female mice.
The first experiment aimed to determine whether morphine analgesia and tolerance differ between male and female mice using the tail-immersion test. The second experiment evaluated morphine and M3G metabolic kinetics in the blood using LC-MS/MS. Morphine and M3G were also quantified in several central nervous system (CNS) regions after acute and chronic morphine treatment. Finally, the blood-brain barrier permeability of M3G was assessed in male and female mice.
This study demonstrated that female mice showed weaker morphine analgesia. In addition, tolerance appeared earlier in females but the sex discrepancies observed seemed to be due to the initial differences in morphine analgesia rather than to sex-specific mechanisms involving metabolism. Additionally, compared to male mice, female mice showed higher levels of M3G in the blood and in several CNS regions, whereas lower levels of morphine were observed in these brain regions. These differences are attributable mainly to morphine central metabolism, which differed between males and females in pain-related brain regions, consistent with the weaker analgesic effect in females. However, the role of morphine metabolism in analgesic tolerance seems rather limited.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
AVAILABILITY OF MATERIALS AND DATA - The authors declare that materials and data are available for readers.
ABBREVIATIONS
- ACN
- acetonitrile
- AUC
- area under the curve
- AUMC
- area under the first moment curve
- BBB
- blood-brain barrier
- CID
- collision gas
- Cl/F
- clearance over bioavailability
- Cmax
- maximal concentration reached over the time course
- CNS
- central nervous system
- d3-morphine
- morphine bearing three 2H
- LC-MS/MS
- liquid chromatography coupled to tandem mass spectrometry
- lSC
- lumbar spinal cord
- M3G
- morphine-3-glucuronide
- M6G
- morphine-6-glucuronide
- MOR
- mu opioid receptor
- MPE
- maximal possible effect
- MRM
- multiple reaction monitoring mode
- MRT
- mean residence time
- NCA
- non-compartmental analysis
- OB
- olfactory bulb
- OIH
- opioid induced hyperalgesia
- PAG
- periaqueductal gray
- T1/2
- half-life
- UGT
- UDP-glucuronosyl-transferase
- Vdss/F
- volume of distribution at steady-state over bioavailability