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Dimethylarginine dimethylaminohydrolase 1 is involved in spinal nociceptive plasticity

DʼMello, R; Sand, CA; Pezet, S; Leiper, JM; Gaurilcikaite, E; McMahon, SB; Dickenson, AH; (2015) Dimethylarginine dimethylaminohydrolase 1 is involved in spinal nociceptive plasticity. Pain , 156 (10) pp. 2052-2060. 10.1097/j.pain.0000000000000269. Green open access

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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.

Type: Article
Title: Dimethylarginine dimethylaminohydrolase 1 is involved in spinal nociceptive plasticity
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1097/j.pain.0000000000000269
Publisher version: http://dx.doi.org/10.1097/j.pain.0000000000000269
Language: English
Additional information: This is a non-final version of an article published in final form in: DʼMello, R; Sand, CA; Pezet, S; Leiper, JM; Gaurilcikaite, E; McMahon, SB; Dickenson, AH; (2015) Dimethylarginine dimethylaminohydrolase 1 is involved in spinal nociceptive plasticity. Pain, 156 (10) pp. 2052-2060. 10.1097/j.pain.0000000000000269.
Keywords: Action Potentials, Amidohydrolases, Animals, Cells, Cultured, Disease Models, Animal, Ganglia, Spinal, Gene Expression Regulation, Male, Mice, Mice, Inbred C57BL, NG-Nitroarginine Methyl Ester, Nerve Fibers, Nerve Tissue Proteins, Neuronal Plasticity, Nitric Oxide Synthase, Nitrites, Nociception, Rats, Rats, Sprague-Dawley, Spinal Cord, Spinal Cord Dorsal Horn
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1491780
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