Involvement of peripheral adenosine A2 receptors in adenosine A1 receptor-mediated recovery of respiratory motor function after upper cervical spinal cord hemisection.
OBJECTIVE
In an animal model of spinal cord injury, a latent respiratory motor pathway can be pharmacologically activated through central adenosine A1 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 A2 receptors in functional recovery in our model is untested. The objective of this study was to assess the effects of peripherally located adenosine A2 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=12) or excised (H-CBE; n=12). Animals were administered the adenosine A2 receptor agonist, CGS-21680, followed by the A1 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=6) in H-CBI rats induced a significantly greater recovery (58.5 +/- 3.6%) than when DPCPX (42.6 +/- 4.6%) was administered (n=6) alone. In H-CBE rats, prior administration of CGS-21680 (n=6) did not enhance recovery over that induced by DPCPX (n=6) alone. Recovery in H-CBE rats amounted to 39.7 +/- 3.7% and 38.4 + 4.2%, respectively.


CONCLUSIONS
Our results suggest that adenosine A2 receptors located in the carotid bodies can enhance the magnitude of adenosine A1 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.
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan 48202, USA.
Elysia
E
James
Kwaku D
KD
Nantwi
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002344:Carotid Body / Q000187:drug effects / Q000503:physiopathology*; D002574:Cervical Vertebrae / Q000293:injuries; D004357:Drug Synergism; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043683:Receptors, Adenosine A2 / Q000502:physiology*; D012133:Respiratory Paralysis / Q000503:physiopathology*; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D014970:Xanthines / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D010627:Phenethylamines; D043683:Receptors, Adenosine A2; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine