The role fo the adrenergic system in the recovery of motoneuron excitability and spasms after spinal cord injury

  • Author / Creator
    Rank, Michelle Maria
  • Brainstem derived noradrenaline (NA) in the spinal cord functions both to increase motoneuron excitability, by facilitating calcium-mediated persistent inward currents (Ca PICs), and to inhibit sensory afferent transmission to motoneurons (excitatory postsynaptic potentials; EPSPs). Spinal cord injury (SCI) results in a reduction of NA, causing a loss of Ca PICs in motoneurons below the lesion and exaggerated EPSPs to emerge. With time motoneuron Ca PICs gradually recover and are readily triggered by the exaggerated EPSPs, resulting in the development of muscle spasms. The role of the NA in the recovery of Ca PICs and muscle spasms after chronic SCI is examined in this thesis using a rat model of spasticity incorporating both the awake rat (in vivo) and the isolated rat spinal cord (in vitro). Specific activation of the adrenergic α1 receptor with agonists facilitated Ca PIC and spasms, whereas activation of the adrenergic α2 receptor with agonists decreased the EPSPs that trigger spasms. Both receptors were endogenously activated by a ligand in vivo, though the α1 receptor additionally exhibits constitutive activity (activity in the absence of NA), predominantly in vitro. The adrenergic α2 receptor was not found to be endogenously active in vitro. Use of amphetamine in rats, which causes a forced efflux of endogenous NA, confirmed the identity of the endogenous ligand as NA and demonstrated that a residual source of NA capable of facilitating the Ca PIC and spasms persists below a chronic transection. Immunohistochemical labelling for an enzyme involved in the synthesis of NA (dopamine-β-hydroxylase) revealed that NA is not synthesized in the spinal cord below a chronic transection, indicating that the endogenous NA is not intrinsic to the spinal cord. Peripheral injections of NA were used to demonstrate that the residual NA instead originates in the periphery (blood) and is both passively and actively transported across a compromised blood-brain barrier (BBB) after chronic injury. The peripherally derived NA activates central adrenergic receptors to modulate motoneuron excitability, sensory synaptic transmission and muscle spasms after chronic SCI. This novel finding highlights the importance of understanding the adaptations of neurotransmitter systems after injury when developing effective treatment strategies for spasticity.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • 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
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Centre for Neuroscience
  • Supervisor / co-supervisor and their department(s)
    • Gorassini, Monica A. (Biomedical Engineering)
    • Bennett, David J. (Rehabilitation Medicine)
  • Examining committee members and their departments
    • Funk, Gregory D. (Physiology)
    • Whelan, Patrick (University of Calgary)
    • Stein, Richard B. (Physiology)
    • Baker, Glen (Psychiatry)