We have recently discovered a novel anti-inflammatory pathway that directly links the central nervous system to the immune system. Our studies on the effects of adenosine (Ado) on neutrophil accumulation led us to examine whether spinal cord Ado receptor stimulation can directly regulate neutrophil recruitment to peripheral sites. Neutrophil infiltration into dermal inflammatory sites was significantly reduced by adenosine A1 receptor agonists injected through intrathecal catheters. Mechanism studies demonstrated that spinal cord A1 receptor stimulation suppresses central NMDA receptor activity, thereby blocking neutrophil accumulation in peripheral inflammatory sites. The effect is mediated by increasing peripheral tissue levels of adenosine, an anti- inflammatory autacoid that inhibits neutrophil function through A2 receptor activation. This represents a previously unknown pathway by which the central nervous system influences inflammatory responses. The purpose of this proposal is to understand this mechanism more completely as well as extend these studies to novel Ado-regulating agents and chronic models of inflammation. The neural components and spinal cord neurotransmitters responsible for the spinal cord anti-inflammatory actions will be investigated, including the role of excitatory amino acids, spinal afferent, and transcription factors like c-fos. The mechanism of spinal cord mediated increases in tissue Ado and anti- inflammatory action will also be studied, including effects on tissue Ado metabolism, blood flow, cytokine gene expression, and adhesion molecule regulation. Finally, utility of intrathecal adenosine agonists and adenosine kinase inhibitors will be studied in a chronic arthritis model. These studies will provide a basis for understanding the central nervous system-immune system connection as well as explore novel therapeutic targets.
| Sorkin, Linda S; Moore, James; Boyle, David L et al. (2003) Regulation of peripheral inflammation by spinal adenosine: role of somatic afferent fibers. Exp Neurol 184:162-8 |
| Boyle, David L; Moore, James; Yang, Li et al. (2002) Spinal adenosine receptor activation inhibits inflammation and joint destruction in rat adjuvant-induced arthritis. Arthritis Rheum 46:3076-82 |
