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 partici pates in analgesia produced by various drugs. In rats with a hypersensitivi ty state following peripheral nerve injury, spinal administration of an NO donor or l-cysteine alone produced no effect, whereas their combination. wh ich yields s-nitroso-l-cysteine (SNC) powerfully reduced hypersensitivity. In the current study, we examined the ability of SNC to stimulate release o f a known spinal analgesic neurotransmitter, norepinephrine (NE), as a poss ible mechanism of analgesic action of NO in the spinal cord. SNC (but not t he NO donor alone or decomposed SNC) produced a concentration-dependent rel ease 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 trans porter. SNC-induced NE release was partially Na+ dependent, but largely Ca2 + independent. NE uptake inhibitors partially antagonized the effect of SNC , but guanylate cyclase inhibitors were without effect. These data are ther efore consistent with NO stimulating NE release in the spinal cord via reac tion with thiol containing compounds, such as cysteine, entry into NE termi nals via active transport, and production of both exocytotic and carrier me diated release. (C) 2000 Elsevier Science B.V. All rights reserved.