Adenosinergic mechanisms underlying recovery of diaphragm motor function following upper cervical spinal cord injury: potential therapeutic implications

Abstract

Objectives: In adult rats, a latent respiratory motor pathway can be pharmacologically activated with 1,3-dimethylxanthine (theophylline) to restore respiratory-related activity to a hemidiaphragm paralysed by an ipsilateral upper cervical (C2) spinal cord hemisection. The purpose of this review is to describe mechanisms that underlie theophylline-induced recovery of respiratoryrelated function following C2 hemisection and to underscore the therapeutic potential of theophylline therapy in spinal cord injured patients with respiratory deficits.Methods: Theophylline mediates recovery of respiratory-related activity via antagonism of central adenosine A1 receptors. When administered chronically, the drug restores and maintains recovered function. Since theophylline is an adenosine receptor antagonist with affinity for both the adenosine A1 and A2 receptors, we assessed the relative contributions of each receptor to functional recovery. While A1 receptor antagonism plays a predominant role, activation of the A2 receptors by specific agonists subserves the A1 receptor-mediated actions. That is, when an adenosine A2 receptor agonist is administered first, it primes the system such that subsequent administration of the A1 antagonist induces a greater degree of recovered respiratory activity than when the antagonist alone is administered.Results: Chronic oral administration of theophylline in C2 hemisected animals demonstrates that even when animals have been weaned from the drug, theophylline-induced recovered respiratory actions persist. This suggests that in clinical application, it may not be necessary to maintain patients on long-term theophylline. We have shown that recovery of respiratory-related activity in the ipsilateral phrenic nerve can occur spontaneously 3–4 months after C2 hemisection. Theophylline administration after this post-injury period obliterates/negates the recovery function. This indicates strongly that there is therapeutic window (more acutely after injury) for the initiation of theophylline therapy. We have also demonstrated that peripheral (carotid bodies) adenosine A1 receptors can be selectively activated to modulate theophyllineinduced CNS actions. Blocking central adenosine receptors while simultaneously activating peripheral adenosine receptors minimizes the potential of respiratory muscle fatigue with theophylline.Discussion: The significance of the current findings lies in the potential clinical application of theophylline therapy in spinal cord injured patients with respiratory deficits. The ultimate goal of theophylline therapy is to wean ventilator-dependent patients off ventilatory support. Thus far, our animal studies suggest that the onset of theophylline therapy must be soon after injury.