Dimethylarginine dimethylaminohydrolase-1 is involved in spinal nociceptive plasticity.

Richard D'Mello, Claire Alexandra Sand, Sophie Pezet, James Leiper, Egle Gaurilcikaite, Stephen Brendan McMahon, Anthony Dickenson, Manasi Nandi

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Activation of neuronal nitric oxide synthase (nNOS), and consequent production of nitric oxide (NO), contributes to spinal hyperexcitability and enhanced pain sensation. All NOS isoforms are inhibited endogenously by asymmetric dimethylarginine (ADMA), which itself is metabolised by dimethylarginine dimethylaminohydrolase (DDAH). Inhibition of DDAH can indirectly attenuate NO production by elevating ADMA 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 (DRG) and spinal dorsal horn; L-291 (N-[2-Methyoxyethyl]-L-arginine methyl ester), a DDAH-1 inhibitor, reduced NO synthesis in cultured DRG neurons. Spinal application of L-291 decreased N-methyl-D-aspartate (NMDA)-dependent post-discharge and wind-up of dorsal horn sensory neurons - two 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.
Original languageEnglish
Article number26098438
Pages (from-to)2052–2060
Number of pages8
JournalPain
Volume156
Issue number10
DOIs
Publication statusPublished - Oct 2015

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