Research PaperParadoxical effects of continuous high dose gabapentin treatment on autonomic dysreflexia after complete spinal cord injury
Introduction
Along with sensory and motor impairments, traumatic spinal cord injury (SCI) results in a constellation of cardiovascular and autonomic dysfunctions (Hou and Rabchevsky, 2014; Krassioukov et al., 2003; Weaver et al., 2012), notably with injuries above the sixth thoracic (T6) segment that frequently result in the development of a condition termed autonomic dysreflexia (AD). This syndrome is characterized by episodes of volatile and potentially lethal hypertension in response to exaggerated sympathetic reflexes triggered by unperceived afferent stimuli below the injury level. Affected individuals may experience cardiac arrhythmia, pounding headache, anxiety, flushing of the skin and profuse sweating above the lesion during an episode of AD. This episodic disorder can occur frequently throughout the day due to regular filling of the bowel and bladder creating noxious stimuli, or by irregular and less predictable triggers such as pressure sores or ingrown toe nails (Karlsson, 1999). Because of the unpleasant and potentially dangerous manifestations, prevention or effective treatment of AD is one of the highest priorities in the SCI community for enhancing quality of life (Anderson, 2004).
Mechanisms known to contribute to the development of AD include the loss of descending vasomotor modulatory pathways, hyperreactivity of peripheral vasculature to adrenergic stimulation, and a number of maladaptive changes within spinal circuitry influencing sympathetic outflow below the lesion (Krassioukov et al., 1999; Schramm, 2006). Intraspinal changes include sprouting of both unmyelinated afferent c-fibers and ascending propriospinal ‘relay’ projections towards sympathetically-correlated interneurons in the thoracic spinal cord, as well as dynamic alterations of synaptic inputs to decentralized sympathetic preganglionic neurons (SPN) in the thoracolumbar spinal cord. Synapses derived from descending supraspinal projections onto SPN are eliminated within one week after complete spinal transection at the fourth thoracic (T4) segment, but by two weeks after injury there is restoration of synaptic terminals onto SPN derived from spinal interneurons and/or primary afferents below the injury (Llewellyn-Smith and Weaver, 2001). Because the development of AD occurs over weeks after SCI in rodents, it has been suggested that injury induced synaptogenesis onto decentralized SPN contributes to AD pathophysiology (Weaver et al., 1997). Based on seminal electrophysiological studies (Krassioukov et al., 2002), a model of AD development has emerged in which the loss of supraspinal control, coupled with convergence from both primary afferents and propriospinal neurons onto sympathetically correlated interneurons, enhances the transmission of noxious stimuli below the injury to SPN, triggering unrestricted sympathetic reflexes during AD (Rabchevsky, 2006); however, this has yet to be thoroughly examined.
We have reported that weeks following complete T4 spinal transection in rats, the administration of the anticonvulsant neuropathic pain medication gabapentin (GBP) significantly reduces the magnitude of colorectal distension (CRD) induced AD and tail spasticity shortly after treatment, lasting several hours (Rabchevsky et al., 2011; Rabchevsky et al., 2012). The mechanism of this clinically valuable effect, however, remains uncertain. GBP was first developed for the treatment of epilepsy and gained subsequent traction as a treatment for neuropathic pain (reviewed in Sirven, 2010). Despite being a structural analog of y-aminobutyric-acid (GABA) with enhanced blood-brain barrier penetration (Crawford et al., 1987), most studies suggest that its actions are independent of GABAergic modulation. GBP's high-affinity binding site is the L-type calcium channel α2δ subunits on presynaptic terminals (Gee et al., 1996), blocking it decreases intraspinal glutamatergic neurotransmission (Coderre et al., 2007), and large daily doses of GBP are reported to prevent the formation of excitatory glutamatergic synapses in the developing CNS by binding to the α2δ1 calcium channel subunit (Eroglu et al., 2009). However, we have found that injured rats treated with GBP an hour prior to CRD weeks later showed significantly reduced AD, whether or not they were treated once daily with saline versus low-dose (50 mg/kg, i.p.) GBP after SCI (Rabchevsky et al., 2012). Because this appears to favor the notion that acute GBP treatment transiently blocks intraspinal glutamatergic neurotransmission which underlies AD (Maiorov et al., 1997), but not synaptogenesis in the injured spinal cord, per se, we sought to determine whether chronic high-dose GBP treatment beginning immediately after SCI alters the development of AD by modulating synaptogenesis of aforementioned intraspinal pathways.
Section snippets
Telemetry probe implantation
All animal housing conditions, surgical procedures, and postoperative care were conducted according to the University of Kentucky Institutional Animal Care and Use Committee and the National Institutes of Health animal care guidelines. Animals were housed in a temperature and humidity-controlled room with a 12/12-h light/dark cycle. Efforts were made to minimize unnecessary foot traffic and other potential environmental disturbances in the room. One week prior to SCI, a total of 24 naïve 3 to
Results
We had a 13% attrition rate with deaths occurring during recovery in the first week after injury and with similar frequency in the saline and GBP groups (n = 1–2 per group).
Discussion
Based on our documentation that acute GBP administration reduces the severity of experimentally induced AD (Rabchevsky et al., 2011; Rabchevsky et al., 2012), and that daily treatment with high dosage GBP can block the formation of excitatory synapses in the brain and spinal cord (Eroglu et al., 2009; Lau et al., 2017; Yu et al., 2018), we sought to determine whether continuous delivery of high-dose GBP can mitigate the development of AD in association with altered synaptic densities in
Conclusions
Continuous high-dose GBP treatment after complete high-thoracic SCI was found to offer significant benefit in reducing the magnitude of AD evoked by noxious stimulation of the pelvic viscera weeks after injury, which was reflected in anxiolytic effects on hemodynamics during the handling procedures. Both low- and high-dose acute GBP treatments appear to mitigate experimentally induced AD, which may be relevant in controlled clinical settings such as iatrogenic procedures. However, the potential
Acknowledgments
Supported by: NIH/NINDS 5T32 NS077889 (KCE); KSCHIRT #10-10 (AGR); SCoBIRC Chair Endowment (AGR); NIH/NINDS 2P30NS051220.
References (66)
- et al.
Plasticity in respiratory motor neurons in response to reduced synaptic inputs: a form of homeostatic plasticity in respiratory control?
Exp. Neurol.
(2017) - et al.
The sympathetic innervation of the heart: important new insights
Auton. Neurosci.
(2016) - et al.
Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis
Cell
(2009) - et al.
The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel
J. Biol. Chem.
(1996) - et al.
A systematic review of the management of autonomic dysreflexia after spinal cord injury
Arch. Phys. Med. Rehabil.
(2009) - et al.
Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation
Exp. Neurol.
(2007) - et al.
Conditional Sox9 ablation improves locomotor recovery after spinal cord injury by increasing reactive sprouting
Exp. Neurol.
(2016) Segmental organization of spinal reflexes mediating autonomic dysreflexia after spinal cord injury
Prog. Brain Res.
(2006)- et al.
Latest approaches for the treatment of spasticity and autonomic dysreflexia in chronic spinal cord injury
Neurotherapeutics
(2011) Spinal sympathetic interneurons: their identification and roles after spinal cord injury
Prog. Brain Res.
(2006)
New uses for older drugs: the tales of aspirin, thalidomide, and gabapentin
Mayo Clin. Proc.
Locations and morphologies of sympathetically correlated neurons in the T(10) spinal segment of the rat
Brain Res.
Immunostaining of rat brain, spinal cord, sensory neurons and skeletal muscle for calcium channel alpha2-delta (alpha2-delta) type 1 protein
Neuroscience
Changes in immunoreactivity for growth associated protein-43 suggest reorganization of synapses on spinal sympathetic neurons after cord transection
Neuroscience
Central mechanisms for autonomic dysreflexia after spinal cord injury
Prog. Brain Res.
Disordered cardiovascular control after spinal cord injury
Handb. Clin. Neurol.
Vesicular glutamate transporters in the spinal cord, with special reference to sensory primary afferent synapses
J. Comp. Neurol.
Targeting recovery: priorities of the spinal cord-injured population
J. Neurotrauma
Smooth muscle cell alpha2delta-1 subunits are essential for vasoregulation by CaV1.2 channels
Circ. Res.
Undirected compensatory plasticity contributes to neuronal dysfunction after severe spinal cord injury
Brain
Spastic long-lasting reflexes in the awake rat after sacral spinal cord injury
J. Neurophysiol.
A guided tour into subcellular colocalization analysis in light microscopy
J. Microsc.
Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level
Brain
Genetic manipulation of intraspinal plasticity after spinal cord injury alters the severity of autonomic dysreflexia
J. Neurosci.
Ongoing and stimulus-evoked activity of sympathetically correlated neurons in the intermediate zone and dorsal horn of acutely spinalized rats
J. Neurophysiol.
A comparison of the glutamate release inhibition and anti-allodynic effects of gabapentin, lamotrigine, and riluzole in a model of neuropathic pain
J. Neurochem.
Gabapentin as an antiepileptic drug in man
J. Neurol. Neurosurg. Psychiatry
A practical guide to evaluating colocalization in biological microscopy
Am. J. Physiol. Cell Physiol.
Incidence of autonomic dysreflexia and silent autonomic dysreflexia in men with spinal cord injury undergoing sperm retrieval: implications for clinical practice
J. Spinal Cord Med.
Rapamycin exacerbates cardiovascular dysfunction after complete high-thoracic spinal cord injury
J. Neurotrauma
Cell death after spinal cord injury is exacerbated by rapid TNF alpha-induced trafficking of GluR2-lacking AMPARs to the plasma membrane
J. Neurosci.
Targeted disruption of the voltage-dependent calcium channel alpha2/delta-1-subunit
Am. J. Physiol. Heart Circ. Physiol.
Gabapentin and Pregabalin for the treatment of anxiety disorders
Clin. Pharmacol. Drug Dev.
Cited by (14)
The gabapentinoid drugs and their abuse potential
2021, Pharmacology and TherapeuticsCitation Excerpt :Increases in gabapentin, pregabalin, and oxycodone prescriptions can increase iatrogenic harm from drug-related morbidity and mortality in the form of misuse, dependence, and poisoning. For instance, Eldahan et al. have highlighted the effects of high-dose gabapentin (GBP) (100 mg/kg i.p. immediately following injury, then 400 mg/kg/day every six hours for 4 weeks) treatments on autonomic dysreflexia (AD), a condition that typically follows injuries above the sixth thoracic (T6) segment (Eldahan et al., 2020). Unperceived afferent stimuli below the injury level result in sympathetic reflexes that typically present as episodes of erratic and fatal hypertension.
Non-invasive approaches to functional recovery after spinal cord injury: Therapeutic targets and multimodal device interventions
2021, Experimental NeurologyCitation Excerpt :The impairments of muscles and bones jeopardize rehabilitation opportunities (Frontera et al., 2006; Clark and Findlay, 2017; Morse et al., 2008). Serious complications commonly arise in the respiratory (van Silfhout et al., 2016), lower urinary tract (Chan et al., 2018; Kanai et al., 2011), gastrointestinal (Holmes and Blanke, 2019; Jogia and Ruitenberg, 2020), cardiovascular (e.g., autonomic dysreflexia; Dorton et al., 2020; Eldahan et al., 2020), and reproductive systems (Stoffel et al., 2018) (Fig. 1c and d). In the USA, ~45.4% of patients were discharged with cervical SCI; the next most frequent injury levels were T12 (~6.1%) and L1 (~4.7%) (i.e., thoracolumbar SCI; 2019 data of The National Spinal Cord Injury Statistical Center: www.nscisc.uab.edu).
Acute post-injury blockade of α2δ-1 calcium channel subunits prevents pathological autonomic plasticity after spinal cord injury
2021, Cell ReportsCitation Excerpt :Genetic differences are key variables that influence SCI pathology and dysautonomia after SCI (Brown and Jacob, 2006; Jacob et al., 2003; Kigerl et al., 2006), so control group data between the different experiments should not be compared directly. The potential for animal strain/species to influence autonomic data after SCI is also highlighted by a study showing that continuous GBP (400 mg/kg/day) increases daily AD events in Wistar rats with T4 transection SCI (Eldahan et al., 2020), although control rats had few events in that study. Because α2δ-1 expression is not limited to neurons, we cannot discount the possibility that benefits of pGBP occur through other α2δ-1-dependent but synapse-independent effects.
Proinflammatory and Immunomodulatory Gene and Protein Expression Patterns in Spinal Cord and Spleen Following Acute and Chronic High Thoracic Injury
2023, Journal of Inflammation ResearchConsequences of spinal cord injury on the sympathetic nervous system
2023, Frontiers in Cellular NeuroscienceFeasibility of gabapentin as an intervention for neurorecovery after an acute spinal cord injury: Protocol
2022, Frontiers in Neurology