Freire et al. REFERENCES Alderton, W. K., Cooper, C. E., and Knowles, R. G. (2001). Nitric oxide synthases: structure, function and inhibition. Biochem. J. 357, 593–615. Aley, K. O., McCarter, G., and Levine, J. D. (1998). Nitric oxide signaling in pain and nociceptor sensitization in the rat. J. Neurosci. 18, 7008–7014. Anderson, C. R. (1992). NADPH diaphorase-positive neurons in the rat spinal cord include a subpopulation of autonomic preganglionic neurons. Neurosci. Lett. 139, 280–284. Barone, P., and Kennedy, H. (2000). Non-uniformity of neocortex: areal heterogeneity of NADPH- diaphorase reactive neurons in adult macaque monkeys. Cereb. Cortex 10, 160–174. Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A., and Freeman, B. A. (1990). Apparent hydroxyl radical production by peroxynitrite: implica- tions for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. U.S.A. 87, 1620–1624. Blaise, G. A., Gauvin, D., Gangal, M., and Authier, S. (2005). Nitric oxide, cell signaling and cell death. Toxicology 208, 177–192. Bredt, D. S., Glatt, C. E., Hwang, P. M., Fotuhi, M., Dawson, T. M., and Snyder, S. H. (1991). Nitric oxide synthase protein and mRNA are dis- cretely localized in neuronal popula- tions of the mammalian CNS together with NADPH diaphorase. Neuron 7, 615–624. Brenman, J. E., and Bredt, D. S. (1996). Nitric oxide signaling in the nerv- ous system. Methods Enzymol. 269, 119–129. Bu l t , H . , B o e c k x s t a e n s , G . E . , Pelckmans, P. A., Jordaens, F. H., Van Maercke, Y. M., and Herman, A. G. (1990). Nitric oxide as an inhibitory non-adrenergic non-cholinergic neu- rotransmitter. Nature 345, 346–347. Calabrese, V., Mancuso, C., Calvani, M., Rizzarelli, E., Butterﬁeld, D. A., and Stella, A. M. (2007). Nitric oxide in the central nervous system: neuro- protection versus neurotoxicity. Nat. Rev. Neurosci. 8, 766–775. Cassina, P., Peluffo, H., Pehar, M., Martinez-Palma, L., Ressia, A., Beckman, J. S., Estevez, A. G., and Barbeito, L. (2002). Peroxynitrite triggers a phenotypic transformation in spinal cord astrocytes that induces motor neuron apoptosis. J. Neurosci. Res. 67, 21–29. Dawson, T. M., Bredt, D. S., Fotuhi, M., Hwang, P. M., and Snyder, S. H. (1991). Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues. Proc. Natl. Acad. Sci. U.S.A. 88, 7797–7801. De Alba, J., Clayton, N. M., Collins, S. D., Colthup, P., Chessell, I., and Knowles, R. G. (2006). GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflamma- tory and neuropathic pain. Pain 120, 170–181. Dun, N. J., Dun, S. L., Wu, S. Y., Forstermann, U., Schmidt, H. H., and Tseng, L. F. (1993). Nitric oxide synthase immunoreactivity in the rat, mouse, cat and squirrel mon- key spinal cord. Neuroscience 54, 845–857. Esplugues, J. V. (2002). NO as a signalling molecule in the nervous system. Br. J. Pharmacol. 135, 1079–1095. Estrada, C., and DeFelipe, J. (1998). Nitric oxide-producing neurons in the neo- cortex: morphological and functional relationship with intraparenchymal microvasculature. Cereb. Cortex 8, 193–203. Firestein, B. L., and Bredt, D. S. (1999). Interaction of neuronal nitric-oxide synthase and phosphofructokinase-M. J. Biol. Chem. 274, 10545–10550. Freire, M. A. M., Franca, J. G., Picanço- Diniz, C.W., and Pereira,A., Jr. (2005). Neuropil reactivity, distribution and morphology of NADPH diaphorase type I neurons in the barrel cortex of the adult mouse. J. Chem. Neuroanat. 30, 71–81. Freire, M. A. M., Oliveira, R. B., Picanço- Diniz, C.W., and Pereira,A., Jr. (2007). Differential effects of methylmercury intoxication in the rat’s barrel ﬁeld as evidenced by NADPH diaphorase histochemistry. Neurotoxicology 28, 175–181. Freire, M. A. M., Tourinho, S. C., Guimarães, J. S., Oliveira, J. L. F., Picanço-Diniz, C. W., Gomes- Leal, W., and Pereira, A., Jr. (2008). Histochemical characterization, distribution and morphometric analysis of NADPH diaphorase neu- rons in the spinal cord of the agouti. Front. Neuroanat. 2, 2. doi: 10.3389/ neuro.3305.3002.2008. Gao, X., Kim, H. K., Chung, J. M., and Chung, K. (2007). Reactive oxygen species (ROS) are involved in enhance- ment of NMDA-receptor phosphor- ylation in animal models of pain. Pain 131, 262–271. Garthwaite, J. (2008). Concepts of neural nitric oxide-mediated transmission. Eur. J. Neurosci. 27, 2783–2802. Guimarães, J. S., Freire, M. A. M., Lima, R. R., Souza-Rodrigues, R. D., Costa, A. M., dos Santos, C. D., Picanço-Diniz, C. W., and Gomes- Leal, W. (2009). Mechanisms of sec- ondary degeneration in the central nervous system during acute neural disorders and white matter damage. Rev. Neurol. 48, 304–310. Guix, F. X., Uribesalgo, I., Coma, M., and Munoz, F. J. (2005). The physi- ology and pathophysiology of nitric oxide in the brain. Prog. Neurobiol. 76, 126–152. Haghikia, A., Mergia, E., Friebe, A., Eysel, U. T., Koesling, D., and Mittmann, T. (2007). Long-term potentiation in the visual cortex requires both nitric oxide recep- tor guanylyl cyclases. J. Neurosci. 27, 818–823. Hassiotis, M., Paxinos, G., and Ashwell, K. W. (2005). Cyto- and che- moarchitecture of the cerebral cortex of an echidna (Tachyglossus aculeatus). II. Laminar organization and synaptic density. J. Comp. Neurol. 482, 94–122. Henry, O. (1999). Frugivory and the importance of seeds in the diet of the orange-rumped agouti (Dasyprocta leporina) in French Guiana. J. Trop. Ecol. 15, 291–300. Hobbs, A. J., and Ignarro, L. J. (1996). Nitric oxide-cyclic GMP signal trans- duction system. Methods Enzymol. 269, 134–148. Holscher, C. (1997). Nitric oxide, the enig- matic neuronal messenger: its role in synaptic plasticity. Trends Neurosci. 20, 298–303. Hope, B. T., Michael, G. J., Knigge, K. M., and Vincent, S. R. (1991). Neuronal NADPH diaphorase is a nitric oxide synthase. Proc. Natl. Acad. Sci. U.S.A. 88, 2811–2814. Hopper, R. A., and Garthwaite, J. (2006). Tonic and phasic nitric oxide signals in hippocampal long-term potentiation. J. Neurosci. 26, 11513–11521. Huang, Z., Huang, P. L., Panahian, N., Dalkara, T., Fishman, M. C., and Moskowitz, M. A. (1994). Effects of cerebral ischemia in mice deﬁcient in neuronal nitric oxide synthase. Science 265, 1883–1885. Iadecola, C., Zhang, F., Casey, R., Nagayama, M., and Ross, M. E. (1997). Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J. Neurosci. 17, 9157–9164. Ignarro, L. J., Buga, G. M., Wood, K. S., Byrns,R.E.,and Chaudhuri,G.(1987). Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc. Natl. Acad. Sci. U.S.A. 84, 9265–9269. Ikeda, H., Stark, J., Fischer, H.,Wagner, M., Drdla, R., Jager, T., and Sandkuhler, J. (2006). Synaptic ampliﬁer of inﬂam- matory pain in the spinal dorsal horn. Science 312, 1659–1662. Ji, R. R., Kohno, T., Moore, K. A., and Woolf, C. J. (2003). Central sensitization and LTP: do pain and Nitric oxide and pain memory share similar mechanisms? Trends Neurosci. 26, 696–705. Kawase, M., Kinouchi, H., Kato, I., Akabane, A., Kondo, T., Arai, S., Fujimura, M., Okamoto, H., and Yoshimoto, T. (1996). Inducible nitric oxide synthase following hypoxia in rat cultured glial cells. Brain Res. 738, 319–322. Knowles, R. G., and Moncada, S. (1994). Nitric oxide synthases in mammals. Biochem. J. 298 (Pt 2), 249–258. Lam, H. H., Hanley, D. F., Trapp, B. D., Saito, S., Raja, S., Dawson, T. M., and Yamaguchi, H. (1996). Induction of spinal cord neuronal nitric oxide syn- thase (NOS) after formalin injection in the rat hind paw. Neurosci. Lett. 210, 201–204. Lipton, S. A., Choi, Y. B., Pan, Z. H., Lei, S. Z., Chen, H. S., Sucher, N. J., Loscalzo, J., Singel, D. J., and Stamler, J. S. (1993). A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364, 626–632. Lipton, S. A., and Rosenberg, P. A. (1994). Excitatory amino acids as a ﬁnal com- mon pathway for neurologic disorders. N. Engl. J. Med. 330, 613–622. Lipton, S.A., Singel, D. J., and Stamler, J. S. (1994). Nitric oxide in the central nervous system. Prog. Brain Res. 103, 359–364. Luth, H. J., Hedlich, A., Hilbig, H., Winkelmann, E., and Mayer, B. (1994). Morphological analyses of NADPH- diaphorase/nitric oxide synthase posi- tive structures in human visual cortex. J. Neurocytol. 23, 770–782. Marletta, M. A. (1993). Nitric oxide syn- thase structure and mechanism. J. Biol. Chem. 268, 12231–12234. Marletta, M. A. (1994). Nitric oxide syn- thase: aspects concerning structure and catalysis. Cell 78, 927–930. Marletta, M. A., Hurshman, A. R., and Rusche, K. M. (1998). Catalysis by nitric oxide synthase. Curr. Opin. Chem .Biol. 2, 656–663. Marsala, J., Kluchova, D., and Marsala, M. (1997). Spinal cord gray matter layers rich in NADPH diaphorase-positive neurons are refractory to ischemia- reperfusion-induced injury: a his- tochemical and silver impregnation study in rabbit. Exp. Neurol. 145, 165–179. Mendell, L. M., and Wall, P. D. (1964). Presynaptic hyperpolarization: a role for ﬁne afferent ﬁbres. J. Physiol. 172, 274–294. Milligan, E. D., and Watkins, L. R. (2009). Pathological and protective roles of glia in chronic pain. Nat. Rev. Neurosci. 10, 23–36. Mizukawa, K., Vincent, S. R., McGeer, P. L., and McGeer, E. G. (1989). Frontiers in Neuroscience www.frontiersin.org September 2009 | Volume 3 | Issue 2 | 180