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Reversal of chronic pain by activation of single GABAA receptor subtypes


Ralvenius, William T. Reversal of chronic pain by activation of single GABAA receptor subtypes. 2015, University of Zurich, Faculty of Science.

Abstract

SUMMARY The ability to perceive pain is a basic property of humans and of all other higher order animals. The primary role of pain sensation and nociception (that is, the neuronal activity encoding pain) is to protect against potentially harmful threats arriving from the environment or the body interior. Pain can however also become dysfunctional and persist for extended periods of time without an apparent benefit, instead becoming a major burden that requires medical attention. Chronic pain is a major socio-economic challenge, which – despite scientific advances in the understanding of its causes – remains poorly responsive to the drugs available on the market today. Recent insights into the mechanisms of chronic pain states suggest that a common factor for many kinds of persistent pain states is a loss of inhibition in spinal cord circuits that normally control nociceptive input to the brain. The so- called benzodiazepines – first marketed by Hoffmann-La Roche in the 1960s – are drugs that facilitate synaptic inhibition throughout the CNS and have as such the potential to reverse pathological disinhibition. Benzodiazepines facilitate inhibition by increasing the activity of γ-aminobutyric acid (GABA) at its receptor, a heteropentameric anion permeable ion channel. Although rodent studies have shown that pathologically increased pain sensitivity can be normalized by intrathecal (spinal) injection of benzodiazepines, these drugs do not exert clinically relevant analgesia in human patients, at least not after systemic application.
In this thesis, I have tested the hypothesis that benzodiazepines reverse pathological pain after systemic application if their action is restricted to well-defined subtypes of GABAA receptors. Using GABAA receptor point-mutated mice, I was able to demonstrate that selective targeting of GABAA receptors that contain the α2 subunit (α2-GABAA) receptors evoke pronounced pain relief in the absence of confounding and undesired sedation. I could also confirm previous findings that had proposed that activation of the same GABAA receptors induces anxiolysis and muscle relaxation. Importantly, selective targeting of α2- GABAA receptors avoided several unwanted effects of classical non-selective benzodiazepines including sedation, impairment of motor coordination, and the progressive loss of therapeutic efficacy over time. Using mice in which the action of classical benzodiazepine agonists was restricted to only a single GABAA receptor subtype, I could also propose a new hypothesis explaining why classical benzodiazepines lack clinically relevant analgesic properties. For two clinically used benzodiazepines (diazepam and midazolam), I could demonstrate that strong α1-GABAA receptor-mediated sedation occurs already at doses.

Abstract

SUMMARY The ability to perceive pain is a basic property of humans and of all other higher order animals. The primary role of pain sensation and nociception (that is, the neuronal activity encoding pain) is to protect against potentially harmful threats arriving from the environment or the body interior. Pain can however also become dysfunctional and persist for extended periods of time without an apparent benefit, instead becoming a major burden that requires medical attention. Chronic pain is a major socio-economic challenge, which – despite scientific advances in the understanding of its causes – remains poorly responsive to the drugs available on the market today. Recent insights into the mechanisms of chronic pain states suggest that a common factor for many kinds of persistent pain states is a loss of inhibition in spinal cord circuits that normally control nociceptive input to the brain. The so- called benzodiazepines – first marketed by Hoffmann-La Roche in the 1960s – are drugs that facilitate synaptic inhibition throughout the CNS and have as such the potential to reverse pathological disinhibition. Benzodiazepines facilitate inhibition by increasing the activity of γ-aminobutyric acid (GABA) at its receptor, a heteropentameric anion permeable ion channel. Although rodent studies have shown that pathologically increased pain sensitivity can be normalized by intrathecal (spinal) injection of benzodiazepines, these drugs do not exert clinically relevant analgesia in human patients, at least not after systemic application.
In this thesis, I have tested the hypothesis that benzodiazepines reverse pathological pain after systemic application if their action is restricted to well-defined subtypes of GABAA receptors. Using GABAA receptor point-mutated mice, I was able to demonstrate that selective targeting of GABAA receptors that contain the α2 subunit (α2-GABAA) receptors evoke pronounced pain relief in the absence of confounding and undesired sedation. I could also confirm previous findings that had proposed that activation of the same GABAA receptors induces anxiolysis and muscle relaxation. Importantly, selective targeting of α2- GABAA receptors avoided several unwanted effects of classical non-selective benzodiazepines including sedation, impairment of motor coordination, and the progressive loss of therapeutic efficacy over time. Using mice in which the action of classical benzodiazepine agonists was restricted to only a single GABAA receptor subtype, I could also propose a new hypothesis explaining why classical benzodiazepines lack clinically relevant analgesic properties. For two clinically used benzodiazepines (diazepam and midazolam), I could demonstrate that strong α1-GABAA receptor-mediated sedation occurs already at doses.

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Additional indexing

Item Type:Dissertation (monographical)
Referees:Zeilhofer Hanns Ulrich
Communities & Collections:UZH Dissertations
Dewey Decimal Classification:Unspecified
Language:English
Place of Publication:Zürich
Date:2015
Deposited On:22 Mar 2019 15:15
Last Modified:07 Apr 2020 07:17
Number of Pages:125
OA Status:Green
Related URLs:https://www.recherche-portal.ch/primo-explore/fulldisplay?docid=ebi01_prod010535797&context=L&vid=ZAD&search_scope=default_scope&tab=default_tab&lang=de_DE (Library Catalogue)

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