S-nitroso-l-cysteine releases norepinephrine in rat spinal synaptosomes

Although nitric oxide (NO) participates in development of hypersensitivity states in the spinal cord thought to underlie chronic pain, it also participates in analgesia produced by various drugs. In rats with a hypersensitivity state following peripheral nerve injury, spinal administration of an NO donor or l-cysteine alone produced no effect, whereas their combination, which yields s-nitroso-l-cysteine (SNC) powerfully reduced hypersensitivity. In the current study, we examined the ability of SNC to stimulate release of a known spinal analgesic neurotransmitter, norepinephrine (NE), as a possible mechanism of analgesic action of NO in the spinal cord. SNC (but not the NO donor alone or decomposed SNC) produced a concentration-dependent release of NE from rat spinal cord synaptosomes. The d-isomer of SNC was less potent than the l-isomer, and the effect of SNC was partially blocked by l-, but not d-leucine, implicating an interaction with the l-amino acid transporter. SNC-induced NE release was partially Na(+) dependent, but largely Ca(2+) independent. NE uptake inhibitors partially antagonized the effect of SNC, but guanylate cyclase inhibitors were without effect. These data are therefore consistent with NO stimulating NE release in the spinal cord via reaction with thiol containing compounds, such as cysteine, entry into NE terminals via active transport, and production of both exocytotic and carrier mediated release.