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Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Division of Biological Research on Drug Dependence)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Division of Biological Research on Drug Dependence)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Division of Biological Research on Drug Dependence)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (The Beijer Laboratory)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The use of opioid analgesics to treat non-cancer pain has increased over the years.  Many chronic pain patients suffer from numerous adverse effects, such as reduced quality of life, development of dependence, and cognitive impairments. Cognitive processes are regulated by several systems, one of which involves growth hormone (GH) and its secondary mediator insulin-like growth factor-1 (IGF-1), but also receptors such as the N-methyl-D-aspartate (NMDA)-receptor complex. In the laboratory, repeated injections are commonly used to establish animal models of long-term or chronic drug exposure. However, in the present study, we aimed to mimic a more human dose regimen using constant drug delivery provided by mini-osmotic pumps implanted subcutaneously in male Sprague Dawley rats. After developing opioid tolerance the cognitive function of rats was studied. Spatial learning and memory were evaluated using the Morris water maze (MWM). Moreover, gene expression related to the GH/IGF-1-axis and the NMDA-receptor system were analyzed using quantitative PCR (qPCR) and the levels of IGF-1 in plasma were examined with ELISA. Our results demonstrate that rats exposed to morphine for 27 days display memory impairments in the MWM probe trial. However, the behavioral effects of chronic morphine treatment were not accompanied by any significant differences in terms of mRNA expression or IGF-1 plasma concentration. The animal model used in this study provides a simple and suitable way to investigate the behavioral and neurochemical effects of chronic opioid treatment similar to the exposure seen in human pain patients.

Keyword [en]
Morphine, Morris water maze, mini-osmotic pumps, memory, insulin-like growth factor-1, N-metyl-D-aspartate
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-317302OAI: oai:DiVA.org:uu-317302DiVA: diva2:1081109
Funder
Swedish Research Council, 9459Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2017-03-13 Created: 2017-03-13 Last updated: 2017-03-15
In thesis
1. Growth hormone in the brain: Focus on cognitive function
Open this publication in new window or tab >>Growth hormone in the brain: Focus on cognitive function
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cognitive impairments are an increasing health problem worldwide. In the developed countries, the average life expectancy has dramatically increased over the last decades, and with an elderly population more cases of cognitive impairments appear. Age, genetics, and different medical conditions such as diabetes mellitus, and substance use disorders may all contribute to declined cognitive ability. Physiological functions also decrease with increasing age, as does the activity of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Interestingly, both GH and IGF-1 are recognized for their neuroprotective effects and cognitive enhancement. The overall aim of this thesis was to investigate the impact of the somatotrophic axis (i.e. GH/IGF-1 axis) in rodents with cognitive deficiencies induced by diabetes or long-term drug exposure. For the first time cognitive impairments were characterized in diabetic mice using a spatial learning and memory task called the Barnes maze (BM). In diabetic mice, impaired learning in the BM was associated with decreased expression of the GH receptor (GHR) in the frontal cortex, a region important for e.g. working memory. Treatment with GH reversed certain cognitive impairments seen in diabetic animals. In rats treated with gamma-hydroxybutyrate (GHB), a significant decrease of Igf1 mRNA expression in the frontal cortex was observed. This observation may explain the impaired cognitive function previously seen following GHB administration. Furthermore, rats exposed to chronic morphine delivered in mini-osmotic pumps displayed memory impairments in the Morris water maze (MWM), an effect that seems to be associated with the composition of the N-methyl-d-aspartate (NMDA) receptor complex in the frontal cortex. In conclusion, the result strengthens the evidence for GH being a cognitive enhancer. Moreover, the result within this thesis identifies the frontal cortex as an important brain region, where gene expression related to the somatotrophic system is affected in rodents with cognitive impairments. The thesis especially emphasizes the importance of the local somatotrophic system in the brain with regard to cognitive function.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 79 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 227
Keyword
Growth hormone, central nervous system, cognition, morphine, gamma-hydroxybutyrate, diabetes, Barnes maze, Morris water maze, mice, rats
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-317305 (URN)978-91-554-9854-2 (ISBN)
Public defence
2017-05-05, B42, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Funder
Swedish Research Council, 9459Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2017-04-12 Created: 2017-03-15 Last updated: 2017-04-21

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