Actions of specific adenosine receptor A1 and A2 agonists and antagonists in recovery of phrenic motor output following upper cervical spinal cord injury in adult rats.

Abstract

1. Previous studies from our laboratory have established that a latent respiratory motor pathway can be activated to restore function to a hemidiaphragm paralysed by upper cervical (C2) spinal cord hemisection during a reflex known as the 'crossed phrenic phenomenon'. In addition, theophylline, a general adenosine A1 and A2 receptor antagonist, can activate the latent pathway by acting centrally through antagonism at adenosine receptors. 2. The present study was designed to assess the relative contributions of adenosine A1 and A2 receptors in inducing functional recovery in our model of spinal cord injury. Specific adenosine A1 and A2 agonists and antagonists were used in an electrophysiological study. 3. Our results demonstrate that, in hemisected rats, systemic administration of the adenosine A1 receptor-specific antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) restores, in a dose-dependent manner, phrenic nerve respiratory related output that is lost following hemisection. Furthermore, DPCPX augments respiratory activity in non-injured animals. The A2 receptor agonist CGS-21680 mediates its effects by predominantly acting on peripheral rather than central nervous system (CNS) receptors. CGS-21680 modulates respiratory related phrenic nerve activity in non-injured animals by enhancing tonic activity, but does not induce recovery of phrenic nerve activity in hemisected animals in the majority of cases. When CGS-21680 was administered prior to DPCPX in hemisected rats, the magnitude of recovery of respiratory function was significantly greater than that elicited by DPCPX alone. However, when the A2 receptor agonist was administered after DPCPX, the magnitude of recovery was virtually unchanged, whereas activity in the right phrenic nerve was significantly enhanced. The A1 receptor agonist N6-cyclohexyladenosine depressed respiratory activity in non-injured, as well as hemisected, rats. The A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine did not affect respiratory activity. 4. We conclude that while antagonism at central adenosine A1 receptors mediates functional restitution in hemisected animals, activation of A2 receptors located outside of the CNS subserves the A1 receptor-mediated respiratory recovery.