Systemic hypertonic saline enhances glymphatic spinal cord delivery of lumbar intrathecal morphine
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Systemic hypertonic saline enhances glymphatic spinal cord delivery of lumbar intrathecal morphine. / Blomqvist, Kim J.; Skogster, Moritz O.B.; Kurkela, Mika J.; Rosenholm, Marko P.; Ahlström, Fredrik H.G.; Airavaara, Mikko T.; Backman, Janne T.; Rauhala, Pekka V.; Kalso, Eija A.; Lilius, Tuomas O.
In: Journal of Controlled Release, Vol. 344, 2022, p. 214-224.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Systemic hypertonic saline enhances glymphatic spinal cord delivery of lumbar intrathecal morphine
AU - Blomqvist, Kim J.
AU - Skogster, Moritz O.B.
AU - Kurkela, Mika J.
AU - Rosenholm, Marko P.
AU - Ahlström, Fredrik H.G.
AU - Airavaara, Mikko T.
AU - Backman, Janne T.
AU - Rauhala, Pekka V.
AU - Kalso, Eija A.
AU - Lilius, Tuomas O.
N1 - Publisher Copyright: © 2022 The Authors
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Analgesia
KW - Drug delivery
KW - Glymphatic system
KW - Opioids
KW - Osmosis
KW - Spinal cord
U2 - 10.1016/j.jconrel.2022.03.022
DO - 10.1016/j.jconrel.2022.03.022
M3 - Journal article
C2 - 35301056
AN - SCOPUS:85126518281
VL - 344
SP - 214
EP - 224
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -
ID: 344805936