Involvement of Peripheral Adenosine A2 Receptors in Adenosine A1 Receptor-Mediated Recovery of Respiratory Motor Function After Upper Cervical Spinal Cord Hemisection

Abstract

Background/Objective: In an animal model of spinal cord injury, a latent respiratory motor pathway can be pharmacologically activated through central adenosine A 1 receptor antagonism to restore respiratory function after cervical (C2) spinal cord hemisection that paralyzes the hemidiaphragm ipsilateral to injury. Although respiration is modulated by central and peripheral mechanisms, putative involvement of peripheral adenosine A 2 receptors in functional recovery in our model is untested. The objective of this study was to assess the effects of peripherally located adenosine A 2 receptors on recovery of respiratory function after cervical (C2) spinal cord hemisection.Methods: Respiratory activity was electrophysiologically assessed (under standardized recording conditions) in C2-hemisected adult rats with the carotid bodies intact (H-CBI; n ¼ 12) or excised (H-CBE; n ¼ 12). Animals were administered the adenosine A 2 receptor agonist, CGS-21680, followed by the A 1 receptor antagonist, 1, 3-dipropyl-8-cyclopentylxanthine (DPCPX), or administered DPCPX alone. Recovered respiratory activity, characterized as drug-induced activity in the previously quiescent left phrenic nerve of C2-hemisected animals in H-CBI and H-CBE rats, was compared. Recovered respiratory activity was calculated by dividing drug-induced activity in the left phrenic nerve by activity in the right phrenic nerve.Results: Administration of CGS-21680 before DPCPX (n ¼ 6) in H-CBI rats induced a significantly greater recovery (58.5 6 3.6%) than when DPCPX (42.6 6 4.6%) was administered (n ¼ 6) alone. In H-CBE rats, prior administration of CGS-21680 (n ¼ 6) did not enhance recovery over that induced by DPCPX (n ¼ 6) alone. Recovery in H-CBE rats amounted to 39.7 6 3.7% and 38.4 þ 4.2%, respectively.Conclusions: Our results suggest that adenosine A 2 receptors located in the carotid bodies can enhance the magnitude of adenosine A 1 receptor-mediated recovery of respiratory function after C2 hemisection. We conclude that a novel approach of targeting peripheral and central adenosine receptors can be therapeutically beneficial in alleviating compromised respiratory function after cervical spinal cord injury.

Recovery of respiratory activity after C2 hemisection (C2HS): Involvement of adenosinergic mechanisms

“…The authors suggested that while spinal mechanisms are involved in mediating long term facilitation, putative involvement of adenosine receptors in the carotid body may also be involved (Golder et al, 2008). The assertion is in agreement with previous findings from our lab (Bae et al, 2005; James and Nantwi, 2006). In our lab we observed that systemic administration (0.5-2.0 mg/kg, i.v.)…”

Effect of Spinal Cord Injury on the Respiratory System: Basic Research and Current Clinical Treatment Options

“…Followup experiments indicated that theophylline acted primarily through the adenosine-A 1 receptor (60), but the magnitude of the recovery could be further enhanced by targeting both A1 and A2 receptors. Specifically, studies that simultaneously targeted central A1 receptors (DPCPX, a specific A1-receptor antagonist) and peripheral A2 receptor CGS-21680 (a peripherally specific A2-receptor agonist) enhanced the magnitude of recovered function over that attained by A1-receptor blockade alone (61,62).…”

Differential Expression of Adenosine A1and A2AReceptors After Upper Cervical (C2) Spinal Cord Hemisection in Adult Rats

“…Although central antagonism of adenosine A 1 receptors mediates functional recovery, it has also been demonstrated that although adenosine A 2A receptors do not appear to mediate recovery after injury, activation of peripherally located adenosine A 2A receptors by specific agonists can enhance and/or subserve the centrally mediated adenosine A 1 receptor effect (14,15). Recently, by using immunohistochemistry and in-situ hybridization, we demonstrated a positive colocalization of adenosine A 1 receptor mRNA and immunoreactivity (protein) within the phrenic motoneurons of the ventral horns of the cervical spinal cord (16).…”