title: Dimethylarginine dimethylaminohydrolase 1 is involved in spinal nociceptive plasticity.
abstract: Activation of neuronal nitric oxide synthase, and consequent production of nitric oxide (NO), contributes to spinal hyperexcitability and enhanced pain sensation. All NOS isoforms are inhibited endogenously by asymmetric dimethylarginine, which itself is metabolised by dimethylarginine dimethylaminohydrolase (DDAH). Inhibition of DDAH can indirectly attenuate NO production by elevating asymmetric dimethylarginine concentrations. Here, we show that the DDAH-1 isoform is constitutively active in the nervous system, specifically in the spinal dorsal horn. DDAH-1 was found to be expressed in sensory neurons within both the dorsal root ganglia and spinal dorsal horn; L-291 (NG-[2-Methoxyethyl]-L-arginine methyl ester), a DDAH-1 inhibitor, reduced NO synthesis in cultured dorsal root ganglia neurons. Spinal application of L-291 decreased N-methyl-D-aspartate-dependent postdischarge and windup of dorsal horn sensory neurons--2 measures of spinal hyperexcitability. Finally, spinal application of L-291 reduced both neuronal and behavioral measures of formalin-induced central sensitization. Thus, DDAH-1 may be a potential therapeutic target in neuronal disorders, such as chronic pain, where elevated NO is a contributing factor.
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom London Pain Consortium, Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom Pharmacology and Therapeutics Department, Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom Laboratory of Brain Plasticity, UMR CNRS 8249, ESPCI, Paris, France Nitric Oxide Signaling Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom Wolfson Centre for Age-related Diseases, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: D'Mello
authors.forename: Claire A
authors.initials: CA
authors.lastname: Sand
authors.forename: Sophie
authors.initials: S
authors.lastname: Pezet
authors.forename: James M
authors.initials: JM
authors.lastname: Leiper
authors.forename: Egle
authors.initials: E
authors.lastname: Gaurilcikaite
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McMahon
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Dickenson
authors.forename: Manasi
authors.initials: M
authors.lastname: Nandi
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009412:Nerve Fibers / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D059225:Nociception / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology; D066148:Spinal Cord Dorsal Horn / Q000166:cytology*
chemical_list: D009419:Nerve Tissue Proteins; D009573:Nitrites; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase; D019331:NG-Nitroarginine Methyl Ester