Systemic hypertonic saline enhances glymphatic spinal cord delivery of lumbar intrathecal morphine.

Autor: Blomqvist KJ; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Electronic address: kim.blomqvist@helsinki.fi., Skogster MOB; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Kurkela MJ; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland., Rosenholm MP; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Ahlström FHG; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Airavaara MT; Faculty of Pharmacy and Neuroscience Center, University of Helsinki, Helsinki, Finland., Backman JT; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland., Rauhala PV; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Kalso EA; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki University Hospital and University of Helsinki, Finland; SleepWell Research Programme, Faculty of Medicine, University of Helsinki, Finland., Lilius TO; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Emergency Medicine and Services, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2022 Apr; Vol. 344, pp. 214-224. Date of Electronic Publication: 2022 Mar 14.
DOI: 10.1016/j.jconrel.2022.03.022
Abstrakt: The blood-brain barrier significantly limits effective drug delivery to central nervous system (CNS) targets. The recently characterized glymphatic system offers a perivascular highway for intrathecally (i.t.) administered drugs to reach deep brain structures. Although periarterial cerebrospinal fluid (CSF) influx and concomitant brain drug delivery can be enhanced by pharmacological or hyperosmotic interventions, their effects on drug delivery to the spinal cord, an important target for many drugs, have not been addressed. Hence, we studied in rats whether enhancement of periarterial flow by systemic hypertonic solution might be utilized to enhance spinal delivery and efficacy of i.t. morphine. We also studied whether the hyperosmolar intervention affects brain or cerebrospinal fluid drug concentrations after systemic administration. Periarterial CSF influx was enhanced by intraperitoneal injection of hypertonic saline (HTS, 5.8%, 20 ml/kg, 40 mOsm/kg). The antinociceptive effects of morphine were characterized, using tail flick, hot plate and paw pressure tests. Drug concentrations in serum, tissue and microdialysis samples were determined by liquid chromatography-tandem mass spectrometry. Compared with isotonic solution, HTS increased concentrations of spinal i.t. administered morphine by 240% at the administration level (T13-L1) at 60 min and increased the antinociceptive effect of morphine in tail flick, hot plate, and paw pressure tests. HTS also independently increased hot plate and paw pressure latencies but had no effect in the tail flick test. HTS transiently increased the penetration of intravenous morphine into the lateral ventricle, but not into the hippocampus. In conclusion, acute systemic hyperosmolality is a promising intervention for enhanced spinal delivery of i.t. administered morphine. The relevance of this intervention should be expanded to other i.t. drugs and brought to clinical trials.
(Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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