Acute Post-Injury Blockade of α2δ-1 Receptors Prevents Pathological Autonomic Plasticity after Spinal Cord Injury

Abstract

Spinal cord injury (SCI) damages supraspinal control over spinal autonomic circuitry. As a result, normally innocuous visceral or somatic stimuli (e.g. distended bladder or bowel) trigger pathological dysautonomia caused by uncontrolled reflex activation of sympathetic circuitry. In this report we show that remarkable structural remodeling and synaptic plasticity occurs within spinal autonomic circuitry and that this increases the frequency of autonomic dysreflexia (AD), a life-threatening condition of episodic vascular hypertension that develops progressively in SCI animals and people. We also prove that maladaptive plasticity can be prevented if SCI mice are treated with human equivalent doses of the FDA-approved drug, gabapentin (GBP) before the onset of plasticity. Although GBP is used clinically to treat pain or spasticity after symptom onset, we tested the hypothesis that GBP would prevent maladaptive plasticity if it were used as a prophylactic therapy, starting before the onset of a critical period of enhanced synaptogenesis with maintenance dosing continued for up to 35d post-injury. Using this novel treatment regimen, we show that prophylactic GBP successfully blocks multi-segmental excitatory synaptogenesis within spinal autonomic lamina, abolishes sprouting of autonomic neurons that innervate immune organs and also the sensory afferents that trigger pain and AD. Functionally, this treatment protocol delays the onset and decreases the frequency of spontaneous AD, confers resistance to experimentally induced AD, and protects mice from SCI-induced immune suppression. These data show that GBP could be repurposed as a prophylactic therapy in at-risk individuals with a high-level SCI to prevent the pathological effects of autonomic dysfunction.