Dual role for nitric oxide in dynorphin spinal neurotoxicity

The pharmacological effects of nitric oxide synthase (NOS) inhibitors, NO d onor, and NOS substrate on dynorphin(Dyn) A(1-17) spinal neurotoxicity were studied. Intrathecal (i.t.) pretreatment with both 7-nitroindazole 1 mu mo l, a selective neuronal constitutive NOS (ncNOS) inhibitor, and aminoguanid ine 1 mu mol, 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 H-3-L-a rginine to H-3-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 N-omega-nitro-L-arginine methyl ester (L-NAME) 1 mu mol, a cNOS inhibitor nonselective to both ncNOS and endothelial NOS (ecNOS), did not antagonize Dyn A(1-17) 20 nmol-induce d permanent paraplegia but aggravated Dyn A(1-17) 10 nmol-induced transient paralysis and caused permanent paraplegia. Pretreatment with L-NAME 1 mu m ol 10 min before i.t. Dyn A(1-17) 1.25 and 2.5 mnol, which produced no sign ificant motor dysfunction alone, induced transient paralysis in seven out o f 12 and five out of seven rats, respectively. L-NAME 1 mu mol plus Dyn A(1 -17) 10 nmol induced ncNOS-immunoreactivity expression in ventral horn cell s. Both low and high doses of aminoguanidine (0.2-30 mu mol) did not affect spinal motor function, but high doses of L-NAME (5-20 mu mol) induced dose -dependent hindlimb and tail paralysis associated with spinal cord injury i n normal rats. Pretreatment with low-dose Spermine NONOate, a controlled NO releaser, 0.1 and 0.5 mu mol 10 min before i.t. Dyn A(1-17) 20 nmol, signi ficantly prevented Dyn spinal neurotoxicity, and high-dose Spermine NONOate 2 mu mol i.t. per se induced transient and incomplete paraplegia. But pret reatment with L-Arg 10 mu mol 10 min before Dyn A(1-17) 20 nmol produced on ly partial blockade of Dyn-induced paraplegia. These results demonstrated t hat relatively specific inhibition of ncNOS and iNOS block Dyn-induced incr eases in cNOS and iNOS activities and ncNOS-immunoreactivity in ventral spi nal cord, but nonspecific inhibition of ncNOS and ecNOS aggravated Dyn spin al neurotoxicity. It suggested that both ncNOS and iNOS play an important r ole, but ecNOS might be beneficial in Dyn spinal neurotoxicity. Moderate pr oduction of NO (at vascular level) has an apparently neuroprotective effect , and overproduction of NO (at cellular level) induces neurotoxicity.