Complete thoracic (T) spinal cord injury (SCI) above the T6 level typically results in autonomic dysreflexia, an abnormal hypertensive condition commonly triggered by nociceptive stimuli below the level of SCI. Over-expression of nerve growth factor in the lumbosacral spinal cord induces profuse sprouting of nociceptive pelvic visceral afferent fibers that correlates with increased hypertension in response to noxious colorectal distension. After complete T4 SCI, we evaluated the plasticity of propriospinal neurons conveying visceral input rostrally to thoracic sympathetic preganglionic neurons. The anterograde tracer biotinylated dextran amine (BDA) was injected into the lumbosacral dorsal gray commissure (DGC) of injured/non-transected rats immediately after injury (acute) or 2 weeks later (delayed). At 1 or 2 weeks after delayed or acute injections, respectively, a higher density (p<0.05) of BDA + fibers was found in thoracic dorsal gray matter of injured versus non-transected spinal cords. For corroboration, fast blue (FB) or cholera toxin subunit beta (CTb) was injected into the T9 dorsal horns 2 weeks post-injury/non-transection. After 1 week transport, more retrogradely-labeled (p<0.05) DGC propriospinal neurons (T13-S1) were quantified in injured versus non-transected cords. We also monitored immediate early gene, c-fos, expression following colorectal distension and found increased (p<0.01) c-Fos + cell numbers throughout the DGC after injury. Collectively, these results imply that, in conjunction with local primary afferent fiber plasticity, injury-induced sprouting of DGC neurons may be a key constituent in relaying visceral sensory input to sympathetic preganglionic neurons that elicit autonomic dysreflexia after high thoracic SCI.

J. Neurochem. (2010) 114, 291–301. Abstract In the present study, we evaluated the therapeutic efficacy of acetyl‐l‐carnitine (ALC) administration on mitochondrial dysfunction following tenth thoracic level contusion spinal cord injury (SCI) in rats. Initial results from experiments in vitro with naïve mitochondria showed that, in the absence of pyruvate, ALC can be used as an alternative substrate for mitochondrial respiration. Additionally, when added in vitro to mitochondria isolated from 24 h injured cords, ALC restored respiration rates to normal levels. For administration studies in vivo, injured rats were given i.p. injections of saline (vehicle) or ALC (300 mg/kg) at 15, 30 or 60 min post‐injury, followed by one booster after 6 h. Mitochondria were isolated 24 h post‐injury and assessed for respiration rates, activities of NADH dehydrogenase, cytochrome c oxidase and pyruvate dehydrogenase. SCI significantly (p < 0.05) decreased respiration rates and activities of all enzyme complexes, but ALC treatment significantly (p < 0.05) maintained mitochondrial respiration and enzyme activities compared with vehicle treatment. Critically, ALC administration in vivo at 15 min and 6 h post‐injury versus vehicle, followed once daily for 7 days, significantly (p < 0.05) spared gray matter. In summary, ALC treatment maintains mitochondrial bioenergetics following contusion SCI and, thus, holds great potential as a neuroprotective therapy for acute SCI.

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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 h 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 h mean arterial pressure (MAP) or heart rate (HR) 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 (PSD) 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 useful tool for assessing autonomic function pre- and post-SCI, in conjunction with experimental pharmacotherapeutics for neuropathic pain, such as GBP.

Study DesignUtilizing 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 it acts to decrease presynaptic glutamate release. Since 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.ObjectivesBehavioural 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.SettingLexington, KentuckyMethodsWe employed femoral artery catheterization and radio-telemetric approaches to monitor blood pressure alterations in response to noxious colorectal distension (CRD) weeks after complete SCI.ResultsAt 2-3 weeks post-SCI, acute GBP administration (50 mg/kg, i.p.) significantly attenuated both autonomic dysreflexia and tail spasticity induced by noxious stimuli compared to saline-treated cohorts.ConclusionThese results demonstrate, 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.