Spinal cord adenosine receptor stimulation in rats inhibits peripheral neutrophil accumulation. The role of N-methyl-D-aspartate receptors.
The effect of spinal adenosine receptor ligation on peripheral leukocyte accumulation was studied in two rat models of inflammation. Neutrophil infiltration into dermal inflammatory sites was signficantly reduced by adenosine A1 receptor agonists injected through intrathecal catheters. These effects were reversed by N-methyl-D-aspartate (NMDA), and were mimicked by (+/-)-2-amino-5-phosphonopentanoic acid (AP-5), a glutamate NMDA receptor antagonist. Peripheral adenosine levels, as measured in air pouch exudates, decreased markedly in inflamed pouches but remained near normal after intrathecal treatment with AP-5. Moreover, the antiinflammatory effects of intrathecal A1 receptor agonists and AP-5 were reversed by an adenosine A2 receptor antagonist administered intraperitoneally. Hence, central NMDA receptor activity can regulate neutrophil accumulation in peripheral inflammatory sites by reducing local levels of adenosine, an antiinflammatory autacoid which inhibits neutrophil function through A2 receptor activation. This represents a previously unknown pathway by which the central nervous system influences inflammatory responses.
Bong
G W
GW
Gensia, Inc., San Diego, California 92121, USA.
Rosengren
S
S
Firestein
G S
GS
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002351:Carrageenan / Q000494:pharmacology; D002404:Catheterization; D002490:Central Nervous System / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000187:drug effects; D013116:Spinal Cord / Q000378:metabolism*; D013805:Theobromine / Q000031:analogs & derivatives / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D018691:Excitatory Amino Acid Antagonists; D010627:Phenethylamines; D011422:Propionates; D058915:Purinergic P1 Receptor Antagonists; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); C057837:3,7-dimethyl-1-propargylxanthine; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D003907:Dexamethasone; D002351:Carrageenan; D009195:Peroxidase; D000241:Adenosine; D013805:Theobromine