Dual role for nitric oxide in dynorphin spinal neurotoxicity.

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 micromol, a selective neuronal constitutive NOS (ncNOS) inhibitor, and aminoguanidine 1 micromol, 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 Nomega-nitro-L-arginine methyl ester (L-NAME) 1 micromol, 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 micromol 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 micromol 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 micromol) did not affect spinal motor function, but high doses of L-NAME (5-20 micromol) 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 micromol 10 min before i.t. Dyn A(1-17) 20 nmol, significantly prevented Dyn spinal neurotoxicity, and high-dose Spermine NONOate 2 micromol i.t. per se induced transient and incomplete paraplegia. But pretreatment with L-Arg 10 micromol 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.

Changes in the content of immunoreactive dynorphin in dorsal and ventral spinal cord of the rat in three different conditions.

Previous study in our group demonstrated that dynorphin exerted a significant analgesic effect in spinal cord, and electroacupuncture (EA) of high frequency (100 Hz) produced analgesia which was mediated by dynorphin released in spinal cord. However, no data are up to nowadays available for demonstrating either from anterior horn or from dorsal horn the dynorphin comes. Using radioimmunoassay, we found in the present study that ir-dynorphin content in dorsal horn was 10 times more than in anterior horn, which were 11.24 +/- 0.91 pmol/10 mg protein and 1.08 +/- 0.20 pmol/10 mg protein, respectively. Stimulation of 100 Hz EA for 30 min produced a significant increase of ir-dynorphin content in dorsal horn, in contrast, no change of ir-dynorphin content was found in anterior horn. For the meanwhile, a significant elevation of ir-dynorphin was induced by 100 Hz EA in cerebrospinal fluid. It is concluded according to these data that EA, as a stimulation in physiological condition, elevates the content of ir-dynorphin only in dorsal horn, and induces release of dynorphin in loci. The released dynorphin acts on dorsal horn to mediate the analgesia of EA.

The role of central 5-hydroxytryptamine in acupuncture analgesia.

The role played by central 5-hydroxytryptamine (5-HT) in acupuncture analgesia (AA) has been studied in rats with the tail-flick response as the antinociceptive test. The analgesic effect of acupuncture can be enhanced or lowered by the increment or the decrement of the 5-HT level in the CNS. Furthermore, the turnover rate of 5-HT in the CNS has been found to be greatly facilitated during the period of acupuncture. The results imply that 5-HT in the CNS may be one of the most important neurochemical agents mediating AA.