Dual Role for Nitric Oxide in Dynorphin Spinal Neurotoxicity

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Abstract
The pharmacological effects of nitric oxide synthase (NOS) inhibitors, NO donor, and NOS substrate on dynorphin(Dyn) A(1–17) spinal neurotoxicity were studied. Intrathecal (i.t.) pretreatment with both 7-nitroindazole 1 μmol, a selective neuronal constitutive NOS (ncNOS) inhibitor, and aminoguanidine 1 μmol, a selective inducible NOS (iNOS) inhibitor, 10 min prior to i.t. Dyn A(1–17) 20 nmol significantly ameliorated Dyn-induced neurological outcome. Both 7-nitroindazole and aminoguanidine significantly antagonized the increases of cNOS and iNOS activities measured by conversion of 3H-l-arginine to 3H-l-citrulline in the ventral spinal cord, and blocked the Dyn-induced increases of ncNOS-immunoreactivity in the ventral horn cells 4 h after i.t. Dyn A(1–17) 20 nmol. Pretreatment with Nω-nitro-l-arginine methyl ester (l-NAME) 1 μmol, a cNOS inhibitor nonselective to both ncNOS and endothelial NOS (ecNOS), did not antagonize Dyn A(1–17) 20 nmol-induced permanent paraplegia but aggravated Dyn A(1–17) 10 nmol-induced transient paralysis and caused permanent paraplegia. Pretreatment with l-NAME 1 μmol 10 min before i.t. Dyn A(1–17) 1.25 and 2.5 nmol, which produced no significant motor dysfunction alone, induced transient paralysis in seven out of 12 and five out of seven rats, respectively. l-NAME 1 μmol plus Dyn A(1–17) 10 nmol induced ncNOS-immunoreactivity expression in ventral horn cells. Both low and high doses of aminoguanidine (0.2–30 μmol) did not affect spinal motor function, but high doses of l-NAME (5–20 μmol) induced dose-dependent hindlimb and tail paralysis associated with spinal cord injury in normal rats. Pretreatment with low-dose Spermine NONOate, a controlled NO releaser, 0.1 and 0.5 μmol 10 min before i.t. Dyn A(1–17) 20 nmol, significantly prevented Dyn spinal neurotoxicity, and high-dose Spermine NONOate 2 μmol i.t. per se induced transient and incomplete paraplegia. But pretreatment with l-Arg 10 μmol 10 min before Dyn A(1–17) 20 nmol produced only partial blockade of Dyn-induced paraplegia. These results demonstrated that relatively specific inhibition of ncNOS and iNOS block Dyn-induced increases in cNOS and iNOS activities and ncNOS-immunoreactivity in ventral spinal cord, but nonspecific inhibition of ncNOS and ecNOS aggravated Dyn spinal neurotoxicity. It suggested that both ncNOS and iNOS play an important role, but ecNOS might be beneficial in Dyn spinal neurotoxicity. Moderate production of NO (at vascular level) has an apparently neuroprotective effect, and overproduction of NO (at cellular level) induces neurotoxicity.