Selective Antagonism of A1 Adenosinergic Receptors Strengthens the Neuromodulation of the Sensorimotor Network During Epidural Spinal Stimulation

Abstract

Although epidural spinal stimulation (ESS) results in promising therapeutic effects in individuals with spinal cord injury (SCI), its potential to generate functional motor recovery varies between individuals and remains largely unclear. However, both preclinical and clinical studies indicate the capacity of electrical and pharmacological interventions to synergistically increase the engagement of spinal sensorimotor networks and regain motor function after SCI. This study explored whether selective pharmacological antagonism of the adenosine A1 receptor subtype synergizes with ESS, thereby increasing motor response. We hypothesized that selective pharmacological antagonism of A1 receptors during ESS would produce facilitatory effects in spinal sensorimotor networks detected as an increased amplitude of spinally-evoked motor potentials and sustained duration of ESS induced activity. Terminal experiments were performed in adult rats using trains of stereotyped pulses at 40 Hz delivered at L5 with the local administration to the cord of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). We demonstrated that ESS combined with the blockage of A1 receptors increased the magnitude of the endogenous modulation and postponed the decay of responses that occur during ESS alone. Although DPCPX significantly increased the yield of repetitive stimulation in intact spinal cords, the effects of A1 antagonism on motor evoked responses after an acute spinal transection was not detected. These studies support the future investigation of the optimal dosage, methods of delivery, and systemic effects of the synergistic application of A1 antagonists and spinal stimulation in the intact and injured spinal cord.

Electrical epidural stimulation of the cervical spinal cord: implications for spinal respiratory neuroplasticity after spinal cord injury

“…The efficacy of EES is also frequency dependent for other motor functions such as bladder voiding (31, 307) and inspiratory muscle activation (140,145). In addition, it has been hypothesized that success of EES may also depend on the level of endogenous background spinal modulation coming from descending, ascending, proprioceptive, or cutaneous inputs since 1) spinal and corticospinal excitability is facilitated with the use of specialized EES frequencies believed to correspond to the converging modulatory inputs from other spinal segments (308) and 2) pharmacologically antagonizing inhibition of this background spinal neuromodulation enhances the magnitude of evoked responses and delays decay or potential synaptic fatigue (309). These task-and background modulation-dependent choices of stimulation frequency for locomotor function paradigms suggest a need for continued investigation of frequency-dependent effects in the respiratory system.…”

Complex Electrical Stimulation Systems in Motor Function Rehabilitation after Spinal Cord Injury

“…erapy. In some cases, these pharmacological treatments can enhance the effects of exercise training and epidural stimulation [108]. is combination intervention may target the internal environment of the injured spinal cord to further increase its excitability and enhance the effectiveness of therapeutic electrical stimulation.…”