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Published on: July 29, 2014
Altered brain exposure of morphine in experimental meningitis studied with microdialysis
K Tunblad1, P Ederoth, A Gärdenfors
1Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden. Karin.Tunblad@farmbio.uu.se
Background:
During pathologic conditions such as meningitis and traumatic brain injury the function of the blood-brain barrier (BBB) is disturbed. In the present study we examined the cerebral pharmacokinetic pattern of morphine in the intact brain and during experimentally induced meningitis using a pig model. Secondly, the use of intracerebral microdialysis as a potential tool for monitoring damage in the BBB by studying the pharmacokinetics of morphine is addressed.
Methods:
Six pigs were studied under general anaesthesia. One occipital and two frontal microdialysis probes and one pressure transducer were inserted into the brain tissue. Another probe was placed into the jugularis interna. Morphine 1 mg kg(-1) was administered as a 10-min infusion, and morphine concentrations were then measured for 3 h. Meningitis was subsequently induced by injecting lipopoly-saccharide into the cisterna magna. When meningitis was established, the morphine experiment was repeated.
Results:
The unbound area under the concentration-time curve (AUCu) ratio of morphine in brain to blood was 0.47 (0.19) during the control period, and 0.95 (0.20) (P < 0.001) during meningitis. The increase in the brain/blood AUCu ratio during meningitis implies decreased active efflux and increased passive diffusion of morphine over the BBB. The half-life of morphine in brain was longer than in blood during both periods, and was unaffected by meningitis.
Conclusion:
This study demonstrates that the morphine exposure to the brain is significantly increased during meningitis as compared with the control situation.
Insights
Morphine brain exposure significantly increases during meningitis, indicating altered blood-brain barrier (BBB) function. Intracerebral microdialysis helps monitor BBB damage by studying drug pharmacokinetics.
Area of Science:
- Neuroscience
- Pharmacology
- Physiology
Background:
- Pathologic conditions like meningitis and traumatic brain injury disrupt blood-brain barrier (BBB) function.
- Understanding drug pharmacokinetics across the BBB is crucial for effective treatment.
- The pig model allows for studying complex physiological processes relevant to human conditions.
Purpose of the Study:
- To investigate the cerebral pharmacokinetic pattern of morphine in intact brains versus during experimentally induced meningitis.
- To evaluate intracerebral microdialysis as a tool for monitoring BBB damage by analyzing morphine pharmacokinetics.
Main Methods:
- Utilized a pig model under general anesthesia with implanted microdialysis probes in brain tissue and jugular vein.
- Administered morphine intravenously and measured concentrations over 3 hours.
- Induced meningitis using lipopolysaccharide and repeated morphine pharmacokinetic measurements.
Main Results:
- The unbound area under the concentration-time curve (AUCu) ratio of morphine in brain to blood increased significantly from 0.47 to 0.95 during meningitis (P < 0.001).
- This suggests reduced active efflux and increased passive diffusion of morphine across the BBB during meningitis.
- Morphine's half-life in the brain was longer than in the blood but unaffected by meningitis.
Conclusions:
- Morphine brain exposure is significantly elevated during meningitis compared to normal conditions.
- The BBB permeability to morphine is compromised during meningitis.
- Intracerebral microdialysis is a viable method for assessing BBB integrity through drug pharmacokinetic analysis.
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