The galactosylation of N(ω)-nitro-L-arginine enhances its anti-nocifensive or anti-allodynic effects by targeting glia in healthy and neuropathic mice

Eur J Pharmacol. 2011 Apr 10;656(1-3):52-62. doi: 10.1016/j.ejphar.2011.01.045. Epub 2011 Feb 4.

Abstract

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.

MeSH terms

  • Analgesics / metabolism
  • Analgesics / pharmacology
  • Analgesics / therapeutic use
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / pathology
  • Blood Pressure / drug effects
  • Caspases / genetics
  • Galactose / metabolism*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glucose Transporter Type 3 / metabolism
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / metabolism
  • Hyperalgesia / pathology
  • Hyperalgesia / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Microglia / pathology
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Neuralgia / metabolism
  • Neuralgia / pathology*
  • Neuralgia / physiopathology
  • Neuroglia / cytology
  • Neuroglia / drug effects*
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Nitric Oxide Synthase Type II / metabolism
  • Nitroarginine / metabolism*
  • Nitroarginine / pharmacology*
  • Nitroarginine / therapeutic use
  • Prodrugs / metabolism*
  • Psychomotor Performance / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / injuries
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / physiopathology
  • Time Factors

Substances

  • Analgesics
  • Glucose Transporter Type 3
  • Prodrugs
  • RNA, Messenger
  • Nitroarginine
  • Nitric Oxide Synthase Type II
  • Caspases
  • NG-Nitroarginine Methyl Ester
  • Galactose