Article

Gabapentin for Spasticity and Autonomic Dysreflexia after Severe Spinal Cord Injury

Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536-0509, USA.
Spinal Cord (Impact Factor: 1.8). 01/2011; 49(1):99-105. DOI: 10.1038/sc.2010.67
Source: PubMed

ABSTRACT

Using a complete transection spinal cord injury (SCI) model at the fourth thoracic vertebral level in adult rats, we evaluated whether blocking noxious stimuli below the injury diminishes abnormal somatic and autonomic motor reflexes, manifested in muscular spasticity and hypertensive autonomic dysreflexia, respectively. Gabapentin (GBP) is well tolerated and currently used to manage neuropathic pain in the SCI population; evidence suggests that it acts to decrease presynaptic glutamate release. As clinical evidence indicates that GBP may suppress muscular spasticity in the chronic SCI population, we hypothesized that preventing neurotransmission of noxious stimuli with GBP eliminates a critical physiological link to these distinct, debilitating SCI-induced secondary impairments.
Behavioural assessments of tail muscle spasticity and mean arterial blood pressure responses to noxious somatic and/or visceral stimulation were used to test the effects of GBP on these abnormal reflexes.
Lexington, Kentucky.
We used femoral artery catheterization and radio-telemetric approaches to monitor blood pressure alterations in response to noxious colorectal distension (CRD) weeks after complete SCI.
At 2-3 weeks post-SCI, acute GBP administration (50 mg kg(-1), i.p.) significantly attenuated both autonomic dysreflexia and tail spasticity induced by noxious stimuli compared with saline-treated cohorts.
These results show, for the first time, that a single-pharmacological intervention, GBP, can effectively attenuate the manifestation of both muscular spasticity and autonomic dysreflexia in response to noxious stimuli.

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Available from: Alexander G Rabchevsky
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    • "Presynaptic Ca 2+ availability plays a significant role in frequency modulation of reflexes through modulation of neurotransmitter release (Lev-Tov and Pinco, 1992, Pinco and Lev-Tov, 1993a, Barriere et al., 2008b), and we found that MSR responses were profoundly inhibited by pregabalin under 0.5 Hz stimulations in the D3KO, nearly 40%. It is likely that the inhibition of the MSR pathway by pregabalin is related to the anti-spastic properties of the functionally related α2δ-ligand, gabapentin, (Kitzman et al., 2007, Rabchevsky et al., 2011). Although we observed a ~30% decrease in D3KO LLR amplitude after application, the inhibition by pregabalin at 0.5 Hz was not significant. "
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    • "All surgical procedures were performed under aseptic conditions using sterilized instruments, following the University of Kentucky IACUC and the NIH guidelines. One week following telemetry implantation, the T4 spinal segment of anesthetized (ketamine, 80 mg/kg, i.p.; xylazine 7 mg/kg, i.p.) female Wistar rats (∼225 g) was exposed by T3 laminectomy (n = 12) and the spinal cord was completely transected with a scalpel blade before hemostasis was achieved with gelfoam placed into the resection site, as previously detailed (Cameron et al., 2006; Rabchevsky et al., 2011). Wounds were then irrigated with sterile saline, the muscles sutured using 3-0 vicryl and skin openings stapled with wound clips. "
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    ABSTRACT: We recently reported that the neuropathic pain medication, gabapentin (GBP; Neurontin), significantly attenuated both noxious colorectal distension (CRD)-induced autonomic dysreflexia (AD) and tail pinch-induced spasticity compared to saline-treated cohorts 2-3 weeks after complete high thoracic (T4) spinal cord injury (SCI). Here we employed long-term blood pressure telemetry to test, firstly, the efficacy of daily versus acute GBP treatment in modulating AD and tail spasticity in response to noxious stimuli at 2 and 3 weeks post-injury. Secondly, we determined whether daily GBP alters baseline cardiovascular parameters, as well as spontaneous AD events detected using a novel algorithm based on blood pressure telemetry data. At both 14 and 21 days after SCI, irrespective of daily treatment, acute GBP given 1 hr prior to stimulus significantly attenuated CRD-induced AD and pinch-evoked tail spasticity; conversely, acute saline had no such effects. Moreover, daily GBP did not alter 24 hr mean arterial pressure (MAP) or heart rate values compared to saline treatment, nor did it reduce the incidence of spontaneous AD events compared to saline over the three week assessment period. Power spectral density analysis of the MAP signals demonstrated relative power losses in mid frequency ranges (0.2-0.8 Hz) for all injured animals relative to low frequency MAP power (0.02-0.08 Hz). However, there was no significant difference between groups over time post-injury; hence, GBP had no effect on the persistent loss of MAP fluctuations in the mid frequency range after injury. In summary, the mechanism(s) by which acute GBP treatment mitigate aberrant somatosensory and cardiophysiological responses to noxious stimuli after SCI remain unclear. Nevertheless, with further refinements in defining the dynamics associated with AD events, such as eliminating requisite concomitant bradycardia, the objective repeatability of automatic detection of hypertensive crises provides a potentially.
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    • "Notably, seminal data published by (19) demonstrated that even marginal sub-pial tissue sparing after severe clip compression SCI altered the severity of CRD-induced AD compared to complete transection. Similarly, we have reported (20) that even following severe 350 kdyn T4 contusions with 20 second dwell times we could not demonstrate reproducible manifestation of AD (i.e., hypertention accompanied bradycardia during noxious CRD). As suggested by Mayorov et al. (2001), such discrepancies may be related to the preservation of certain descending vasomotor pathways maintaining excitatory supraspinal input to the sympathetic preganglionic neurons, resulting in persistent sympathetically-mediated cardiovascular reflexes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Using a complete transection spinal cord injury (SCI) model at the fourth thoracic vertebral level in adult rats, we evaluated whether blocking noxious stimuli below the injury diminishes abnormal somatic and autonomic motor reflexes, manifested in muscular spasticity and hypertensive autonomic dysreflexia, respectively. Gabapentin (GBP) is well tolerated and currently used to manage neuropathic pain in the SCI population; evidence suggests that it acts to decrease presynaptic glutamate release. As clinical evidence indicates that GBP may suppress muscular spasticity in the chronic SCI population, we hypothesized that preventing neurotransmission of noxious stimuli with GBP eliminates a critical physiological link to these distinct, debilitating SCI-induced secondary impairments. Behavioural assessments of tail muscle spasticity and mean arterial blood pressure responses to noxious somatic and/or visceral stimulation were used to test the effects of GBP on these abnormal reflexes. Lexington, Kentucky. We used femoral artery catheterization and radio-telemetric approaches to monitor blood pressure alterations in response to noxious colorectal distension (CRD) weeks after complete SCI. At 2-3 weeks post-SCI, acute GBP administration (50 mg kg(-1), i.p.) significantly attenuated both autonomic dysreflexia and tail spasticity induced by noxious stimuli compared with saline-treated cohorts. These results show, for the first time, that a single-pharmacological intervention, GBP, can effectively attenuate the manifestation of both muscular spasticity and autonomic dysreflexia in response to noxious stimuli.
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