Freire et al. Nitric oxide and pain * Correspondence: Antonio Pereira earned a Ph.D. in Biophysics from the Institute of Biophysics of the Federal University of Rio de Janeiro (Brazil) in 1997. After, he spent two and a half years in the Department of Neurobiology at Duke University (USA) as a Research Associate. Currently, he is Associate Professor in the Department of Neuroscience of the Federal University of Rio Grande do Norte (Natal/RN, Brazil). His research interests include various aspects of the morphology and physiology of the mammalian sensory systems, as well as the understanding of higher cognitive functions in humans, such as attention, motor imagery and memory. apereira@ufrnet.br Figure 1 | Nitric oxide synthesis. Diagram showing the synthetic pathway responsible for nitric oxide (NO) production from arginine and O2 and catalyzed by the enzyme nitric oxide synthase (NOS). Cofactors include reduced nicotinamide adenine dinucleotide phosphate (NADPH), tetrahydrobiopterin (BH4), ﬂavin mononucleotide (FMN), and ﬂavin adenine dinucleotide (FAD). Synthesis of NO can be pharmacologically abolished by the action of the N-omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of both nNOS and eNOS. Abbreviations: Ca+2/CaM: Calcium/calmodulin; cGMP: cyclic guanosine monophosphate; GC: guanylate cyclase; PKG: protein kinase G. reactive nitrogen oxide species (RNOS) and reac- tive oxygen species (ROS), such as the powerful oxidant peroxynitrite (ONOO–), that can cause harmful effects on cells, though nitrosative and oxidative stress (Wink et al., 2000). This Janus face of NO, representing its poten- tial for both protective and deleterious effects in the brain, depends mostly on its concentration levels and the identity of the acting enzymatic iso- form (Calabrese et al., 2007; Lipton et al., 1993). The cell signaling activity of NO requires only a low amount generated by both nNOS and eNOS (Esplugues, 2002). The high levels of NO gener- ated by iNOS are responsible for an increase in the amount of both RNOS and ROS (Wink et al., 2000). The toxic effects of NO are mostly medi- ated by its oxidation products, particularly the bio- logical oxidant peroxynitrite (Pacher et al., 2007). Knockout mice lacking the iNOS gene, for instance, are less affected by ischemic brain injury (Iadecola et al., 1997). Oxidative stress is a common feature of the pathogenesis of many neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases (Guix et al., 2005; Moreira et al., 2005). Peroxynitrite generation, speciﬁcally, has been singled out as an important pathogenic mechanism behind those disorders (Pacher et al., 2007; Saha and Pahan, 2006). Interestingly, neu- rons that express nNOS are notoriously resistant to many types of injury, including intoxication by heavy metals (Freire et al., 2007) and NO-induced neurotoxicity (Firestein and Bredt, 1999). In the Peripheral Nervous System (PNS), NO induces the relaxation of smooth muscle cells in the gastrointestinal tract (Bult et al., 1990) and the corpus cavernosum (Toda et al., 2005). In the CNS, NO is a neurotransmitter (Bredt et al., 1991), albeit an unconventional one due to its free dif- fusion through aqueous and lipid compartments. NOS is physiologically active at nanomolar con- centrations and is remarkably stable within this range (Garthwaite, 2008). After being synthesized, NO can act on both postsynaptic and presynaptic structures by way of a GC transduction mecha- nism that eventually increases the intracellular levels of the second messenger cyclic guanos- ine monophosphate (cGMP) (Vincent, 1994). There are hints, however, that other transduc- tion mechanisms might be engaged by NO (see Garthwaite, 2008 for review). NO is involved with other important functions in the normal brain, including regulation of blood ﬂow, neu- rogenesis, and synaptic plasticity (Estrada and DeFelipe, 1998; Holscher, 1997; Moreno-Lopez et al., 2000; Wiesinger, 2001). It is also associated with the long-term potentiation (LTP) of synaptic connections (Brenman and Bredt, 1996) and can act as an anti-apoptotic factor when produced in normal concentrations (see Blaise et al., 2005 for a review). Conversely, following injury of the brain, NO acts as a neurodegenerative agent, contributing to neuronal death (Cassina et al., 2002; Guimarães et al., 2009; Kawase et al., 1996). Several neurodegenerative disorders of the CNS Frontiers in Neuroscience www.frontiersin.org September 2009 | Volume 3 | Issue 2 | 176