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This study has investigated whether the galactosyl ester prodrug of N(ω)-nitro-L-arginine (NAGAL), shows enhanced analgesic efficacy in healthy mice and in models of visceral and neuropathic pain: the writhing test and the spared nerve injury (SNI), respectively. NAGAL was compared to methyl ester pro-drug of N(ω)-nitro-l-arginine (L-NAME), a widely exploited non-specific nitric oxide synthase (NOS) inhibitor, for analgesic potential. The writhing test revealed that the ED(50) value, along with the 95% confidence limit (CL) was 3.82 (1.77-6.04) mg/kg for NAGAL and, 36.75 (20.07-68.37) mg/kg for L-NAME. Notably, NAGAL elicited a greater anti-allodynic effect than L-NAME did in neuropathic mice. Biomolecular and morphological studies revealed that spared nerve injury increased the expressions of pro-inflammatory enzymes (caspase-1) and two glial cell biomarkers: integrin alpha M (ITGAM) and glial fibrillary acidic protein (GFAP) in the spinal cord. Finally, GLUT-3, an isoform of the hexose transporters capable to bind NAGAL and inducible NOS (iNOS), were found to be over-expressed in the activated astrocytes of the spinal cord of neuropathic mice. NAGAL administration normalized expression levels of these biomarkers. NAGAL showed a greater efficacy in inhibiting visceral pain and allodynia than L-NAME possibly by a greater cell permeation through the hexose transporter which is highly over-expressed by activated glia. Copyright © 2011 Elsevier B.V. All rights reserved.

Citation

Catia Giordano, Dario Siniscalco, Daniela Melisi, Livio Luongo, Annalisa Curcio, Marie Soukupova, Enza Palazzo, Ida Marabese, Maria De Chiaro, Maria Grazia Rimoli, Francesco Rossi, Sabatino Maione, Vito de Novellis. The galactosylation of N(ω)-nitro-L-arginine enhances its anti-nocifensive or anti-allodynic effects by targeting glia in healthy and neuropathic mice. European journal of pharmacology. 2011 Apr 10;656(1-3):52-62

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PMID: 21296071

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