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Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
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2005 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 24, no 5, 565-573 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate whether morphine can be transferred along the olfactory pathway to the CNS, thereby circumventingthe blood–brain barrier, after nasal administration to rodents. Radiolabelled and unlabelled morphine were administered via the right nostrilto mice and rats. Olfactory bulbs, brain tissue and blood samples were collected. Morphine-derived radioactivity was measured using liquidscintillation (LS) and the concentrations of morphine and its metabolite morphine-3-glucuronide (M3G) were also assessed with highperformanceliquid chromatography. The location of morphine-derived radioactivity in the rat brain was visualised by autoradiography.Overall, the levels of morphine in the right olfactory bulbs (ROBs) significantly exceeded those in the left olfactory bulbs (LOBs) and braintissue samples 15, 60 and 240 min after right-sided nasal administration. Fifteen minutes after intravenous administration, there were nosignificant differences between olfactory bulbs and the other brain areas. Five minutes after nasal administration, autoradiography revealedradioactivity surrounding the ROB and reaching one of the ventricles in the brain. After 60 min, radioactivity had reached the peripheral partsof the ROB. All the techniques used in this study demonstrate that morphine was transferred along the olfactory pathway to the CNS afternasal administration to rodents.

Place, publisher, year, edition, pages
2005. Vol. 24, no 5, 565-573 p.
Keyword [en]
Olfactory pathway, Nasal drug delivery, Autoradiography, Morphine, Rats
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95787DOI: 10.1016/j.ejps.2005.01.009ISI: 000228318300017PubMedID: 15784346OAI: oai:DiVA.org:uu-95787DiVA: diva2:170127
Available from: 2007-04-19 Created: 2007-04-19 Last updated: 2018-01-13Bibliographically approved
In thesis
1. Olfactory Transfer of Analgesic Drugs After Nasal Administration
Open this publication in new window or tab >>Olfactory Transfer of Analgesic Drugs After Nasal Administration
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nasal administration of analgesics for achieving rapid pain relief is currently a topic of great interest. The blood-brain barrier (BBB) restricts access to the central nervous system (CNS) for several central-acting drugs, such as morphine and dihydroergotamine, which results in a substantial effect delay. Evidence for the olfactory transfer of drugs from the nasal cavity to the CNS after nasal administration, bypassing the BBB, is available for both animals and humans. The aims of this thesis were to study the olfactory transfer of morphine to the CNS after nasal administration, and to compare the nasal transport of analgesic drugs across nasal respiratory and olfactory mucosa.

In vivo studies in rodents demonstrated that morphine is transferred via olfactory pathways to the olfactory bulbs and the longitudinal fissure of the brain after nasal administration. Further, olfactory transfer of morphine significantly contributed to the early high morphine brain hemisphere concentrations seen after nasal administration to rats. Olfactory transfer was tracked by collecting and analysing brain tissue and blood samples after right-sided nasal administration and comparing the results to the situation after i.v. administration. The olfactory transfer was also visualised by brain autoradiography.

In vitro studies indicated that the olfactory mucosa should not be a major barrier to the olfactory transfer of dihydroergotamine or morphine, since transport of these drugs was no more restricted across the olfactory mucosa than across the nasal respiratory mucosa. The in vitro studies were performed using the horizontal Ussing chamber method. This method was further developed to enable comparison of drug transport across nasal respiratory and olfactory mucosa which cannot be achieved in vivo.

In conclusion, these analgesic drugs showed potential for olfactory transfer, and access to the CNS by this route should be further investigated in humans, especially for the drugs with central effects that are currently under development for nasal administration.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 55
Keyword
Pharmaceutics, Nasal administration, Olfactory transfer, Olfactory pathways, Central nervous system, Blood-brain barrier, Nasal respiratory mucosa, Olfactory mucosa, Olfactory bulb, Horizontal Ussing chamber, Morphine, Dihydroergotamine, Rat, Mouse, Swine, Autoradiography, Viability, Powder formulations, Galenisk farmaci
Identifiers
urn:nbn:se:uu:diva-7829 (URN)978-91-554-6871-2 (ISBN)
Public defence
2007-05-11, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2007-04-19 Created: 2007-04-19 Last updated: 2010-03-23Bibliographically approved

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