Gabapentin for spasticity and autonomic dysreflexia after severe spinal cord injury

Abstract

Study design: 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.

Objectives: 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.

Setting: Lexington, Kentucky.

Methods: 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.

Results: 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.

Conclusion: 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.

Figure 1

Illustrative traces of pulsatile arterial pressure (PAP) and heart rate (HR), measured by femoral artery cannulation before, during and after one minute of painful colorectal distension (CRD) in (A) injured rats injected with saline versus (B) injured rats injected with gabapentin (GBP) 14 days post injury. Up and down arrows indicate rectal balloon catheter inflation and deflation, respectively. In GBP-treated rats, the increased MAP and decreased HR (bradycardia) are attenuated in response to CRD. Quantitative analysis (C) confirmed a significant reduction in CRD-induced MAP of more than two-fold with GBP treatment. *p<0.05 n=6 Saline; n=9 GBP (50 mg/kg) Bars represent mean ± SEM

Figure 2

Behavioral responses of the tail musculature to different stimuli 2 weeks following T4 transection (same rats as in Figure 1). A. Average response to stretch 1 hour following the administration of saline (n=6) or gabapentin (GBP; 50 mg/kg; n=9). B. Average response to noxious (pinch) stimulus 1 hour following the administration of saline or GBP. Responses to stretch and pinch were scored on a 5 point scale in which 0 = no spasticity and 5 = severe spasticity. Notice that following administration of GBP there was no response to stretch (A) and a striking decrease in response to pinch stimulus (B). * p<0.05 Bars represent mean ± SEM for visualization purposes only.

Figure 3

Illustrative traces of pulsatile arterial pressure (PAP) and heart rate (HR), measured by telemetric probes in descending aorta before, during and after one minute of noxious colorectal distension (CRD) in (A) injured rats injected with saline versus (B) injured rats injected with gabapentin (GBP) 21 days post injury. With GBP treatment, the increased MAP and decreased HR (bradycardia) appear strikingly attenuated in response to CRD. Quantitative analysis (C) confirmed a significant reduction in CRD-induced MAP of more than two-fold with GBP treatment. While bradycardia appeared to be reduced (D), the variability precluded significant differences. *p<0.05 n=3 Saline; n=3 GBP (50 mg/kg) Bars represent mean ± SEM

Figure 4

The average behavioral response of the tail musculature 3 weeks following T4 transection (same rats as in Figure 3). Panel A represents the average response to light touch 1 hour following the administration of saline (n=3) or GBP (50 mg/kg; n=3). Panel B represents the average response to tail stretch 1 hour following the administration of saline or GBP. Panel C represents the average response to noxious stimulus (tail pinch) 1 hour following the administration of saline or GBP. Response to light touch was scored on a 2 point scale in which 0 = no spasticity and 2 = severe spasticity. Responses to stretch and pinch were scored on a 5 point scale in which 0 = no spasticity and 5 = severe spasticity. Notice that following administration of GBP there was a significant decrease in response to light touch and stretch (A, B), and a striking decrease in response to noxious tail pinch (C). *p<0.05 Bars represent mean ± SEM for visualization purposes only.