The role of CRG-2 protein (murine IP-10) in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis, was tested by blocking crg-2 mRNA synthesis using chronic infusion of antisense oligonucleotides into lumbar subarachnoid space by osmotic minipumps. After injection with myelin basic protein, rats developed hind limb paralysis and their spinal cords showed crg-2 mRNA expression and the presence of inflammation. When antisense phosphorothioate oligonucleotides to crg-2 (AS-PScrg2) or nonspecific oligonucleotides (AS-PSscram) were infused at rates from 0.18 to 5.4 nmol/hr, they caused hind limb paralysis that was clinically different from EAE and tissue necrosis of the spinal cord. Natural phosphodiester (AS-PO) oligonucleotides that were infused at rates from 1.8 to 5.4 nmol/hr had no toxic effects. AS-POcrg2 reduced the initial appearance of crg-2 mRNA and this may be responsible for the significant reduction in the EAE scores at the height of clinical disease. The antisense treatment did not alter inflammation of the spinal cord. While AS-PS oligonucleotides were unsuitable for intrathecal administration, AS-POcrg2 were not toxic and reduced paralysis due to EAE.