TY - JOUR
T1 - Dimethylarginine dimethylaminohydrolase-1 is involved in spinal nociceptive plasticity.
AU - D'Mello, Richard
AU - Sand, Claire Alexandra
AU - Pezet, Sophie
AU - Leiper, James
AU - Gaurilcikaite, Egle
AU - McMahon, Stephen Brendan
AU - Dickenson, Anthony
AU - Nandi, Manasi
PY - 2015/10
Y1 - 2015/10
N2 - 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.
AB - 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.
U2 - 10.1097/j.pain.0000000000000269
DO - 10.1097/j.pain.0000000000000269
M3 - Article
SN - 0304-3959
VL - 156
SP - 2052
EP - 2060
JO - Pain
JF - Pain
IS - 10
M1 - 26098438
ER -