Elsevier

The Journal of Pain

Volume 10, Issue 1, January 2009, Pages 80-89
The Journal of Pain

Original report
Variants of Neural Nitric Oxide Synthase in the Spinal Cord of Neuropathic Rats and Their Effects on Nuclear Factor-κB (NF-κB) Activity in PC12 Cells

https://doi.org/10.1016/j.jpain.2008.07.009Get rights and content
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Abstract

Neuropathic pain due to nerve injury is associated with overactivity of spinal N-methyl-D-aspartate (NMDA) receptors and nitric oxide synthases (NOS). Spinal NOS and NMDA receptors could act in a concerted manner to excite each other in nociceptive signaling. Among the 3 major NOS isoforms, neuronal NOS (nNOS) has the most functional relationship with NMDA receptors through a PDZ-PDZ (PSD-95, Dlg, ZO-1 homology) postsynapse interaction. However, some nNOS variants lack the PDZ domain, which may result in the changes in the interaction with the NMDA receptor and subsequent localization and enzymatic activity. The aim of this study was to determine which nNOS variants are expressed in the spinal cord in neuropathic rats and deduce their role in neuropathic pain by testing the effects of these kinds of nNOS on nuclear factor-κB (NF-κB) activity in PC12 cells. Western blot analysis revealed that there were at least 3 bands of nNOS (155, 135, and 125 kDa) in the spinal cord and, moreover, that nNOS at 135 kDa decreased significantly after development of neuropathic pain. 5′-RACE-PCR and Southern blots determined that the nNOS at 155 and 135 kDa corresponded to nNOSα and nNOSβ, respectively, which was confirmed by RT-PCR. PC12 cells transfected with the nNOSα gene had no effect on NF-κB activity, but nNOSβ without the PDZ domain significantly decreased that in PC12 cells. Considering the importance of spinal NF-κB signaling in neuropathic rat, it could be concluded that changes in spinal nNOS variants and quantity after peripheral nerve injury implicate nNOS in the generation of neuropathic pain.

Perspective

This article presents data demonstrating that nNOS variants change in the spinal cord of the rats after neuropathic pain and result in differential effects on NF-κB activity in PC12 cells. These changes in nNOS variants and their different characteristics may account for the spinal NO paradox role in neuropathic pain. Furthermore, these data suggest that nNOSβ̣ may represent a new therapeutic target for the treatment of chronic neuropathic pain.

Key words

Neural nitric oxide variants
neuropathic rats
NF-κB activity

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