Nitric oxide (NO) acts as a
neurotransmitter or
neuromodulator involving in the modulation of thermal and/or inflammatory
hyperalgesia. The
neuronal nitric oxide synthase (nNOS) is a key
enzyme for NO production in normal neuronal tissues, but its functional role in
chronic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to address the role of nNOS in the central mechanism of complete
Freund's adjuvant (CFA)-induced chronic inflammatory
pain. Targeted disruption of the nNOS gene significantly reduced CFA-induced mechanical
pain hypersensitivity during the maintenance (but not the development) of inflammatory
pain, while it failed to attenuate either development or maintenance of CFA-induced thermal
pain hypersensitivity. Intraperitoneal administration of L-N(G)-nitro-
arginine methyl ester (
L-NAME), a non-specific NOS inhibitor, blocked CFA-evoked thermal and mechanical
pain hypersensitivity at both development (2h) and maintenance (24h) phase in wild type mice, but had no effect in the knockout mice. Furthermore,
intrathecal injection of either
L-NAME or
7-nitroindazole, a selective nNOS inhibitor, markedly attenuated mechanical
pain hypersensitivity at both 2 and 24h after CFA injection. Finally, spinal cord nNOS (but not endothelial NOS or inducible NOS) expression was up-regulated at 24h after CFA injection, occurring mainly in the ipsilateral superficial dorsal horn. Together, these data indicate that spinal cord nNOS may be essential for the maintenance of mechanical
pain hypersensitivity and that it may also be sufficient for the development of mechanical
pain hypersensitivity and for the development and maintenance of thermal
pain hypersensitivity after chronic
inflammation. Our findings suggest that spinal cord nNOS might play a critical role in central mechanisms of the development and/or maintenance of chronic inflammatory
pain.