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Acute Anti-Allodynic Actions of Gabapentin

  • Author / Creator
    Alles, Sascha R
  • This thesis examines the cellular basis of the acute (<1 hour) anti-allodynic actions of the clinically-approved neuropathic pain drug gabapentin (GBP) in rats at the level of the spinal dorsal horn and primary somatosensory cortex. Although the clinical effectiveness of the alpha-2-delta (α2δ) ligand GBP in treatment for neuropathic pain in patients develops over a period of several days, acute administration of clinically-relevant doses (100 mg/kg) of intraperitoneal (IP)-injected GBP significantly reduces behavioural signs of neuropathic pain in rats subject to sciatic chronic constriction injury (CCI) within 30 min. We used ex vivo whole-cell recording and confocal Ca2+ imaging of spinal cord slices and in vivo cortical Ca2+ imaging from GBP-injected rats to identify the neuronal correlates of these acute drug actions. Putative excitatory substantia gelatinosa neurons were identified by their delay firing pattern and putative inhibitory neurons by their tonic firing pattern. When ‘neuropathic’ rats (subject to 7-14 days of sciatic CCI) received an IP injection of 100 mg/kg GBP 30 min prior to euthanasia, excitatory drive to putative excitatory neurons was decreased compared to control saline-injected neuropathic rats. This involved a decreased frequency and amplitude of spontaneous excitatory post-synaptic currents (sEPSC). In contrast, excitatory drive to putative inhibitory neurons increased as a result of increased sEPSC frequency. In putative excitatory neurons from neuropathic animals, rates of action potential discharge in response to depolarising current were decreased by GBP administration. These changes, which were not observed in sham-operated animals, led to an overall decrease in dorsal horn excitability. In vivo imaging studies of rats subject to CCI showed that there is a significant reduction in cortical excitability 10 min following IP injection of 100mg/kg GBP. This result implies that GBP influences cortical responses and affects pain per se within 10 min of systemic injection. It was also shown that bath application of 100 µM GBP to spinal cord slices from neuropathic rats reduced the frequency of sEPSCs in both putative excitatory delay and inhibitory tonic neurons, suggesting that the cell-type specific effects of GBP are lost unless the drug is delivered systemically. These results point to a peripheral or central target of GBP’s acute actions. Many previous studies of the gabapentinoids have failed to identify any major acute effects since these studies have been mainly carried out on naïve animals or with no reference to effects on specific cell types. These results suggest that the acute effectiveness of GBP is specific to neuropathic animals. Since it has been demonstrated that α2δ levels are upregulated in neuropathic rats and that GBP is a α2δ ligand, these results suggest that the levels of α2δ are related to acute gabapentin effectiveness and the rapidity of GBP’s actions. Elucidation of the mechanisms of these acute, cell-type specific actions of gabapentinoids may provide a basis for development of more effective therapeutic approaches.

  • Subjects / Keywords
  • Graduation date
    2016-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3X63BB02
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Centre for Neuroscience
  • Supervisor / co-supervisor and their department(s)
    • Smith, Peter (Neuroscience and Mental Health Institute, University of Alberta)
  • Examining committee members and their departments
    • Zochodne, Douglas (Alberta Diabetes Institute, University of Alberta)
    • Greer, John (Neuroscience and Mental Health Institute, University of Alberta)
    • Luo, David (Anesthesiology, University of California, Irvine)
    • Funk, Gregory (Neuroscience and Mental Health Institute, University of Alberta)