Edited by: Javier DeFelipe, Cajal Institute, Spain Reviewed by: John Garthwaite, University College, UK Marcello G. Rosa, Monash University, Australia * Correspondence: Marco Aurélio M. Freire received his B.Sc. and M.Sc. degrees in Biological Sciences from the Federal University of Pará – UFPA (Belem/PA, Brazil) in 2000 and 2003, respectively, and his Ph.D. in Neuroscience in 2006 from the same institution, evaluating the morphofunctional organization of the isocortex of some distinct species of rodents. During 2009, he was a Visiting Researcher at the Universidad de Chile (Santiago, Chile). His main research interests are Neuroanatomy, Neurophysiology and Experimental Neuropathology, focusing especially on general aspects of the cortical organization, comparative morphophysiology and altered states of the nervous system. freire.m@gmail.com FOCUSED REVIEW published: 15 September 2009 doi: 10.3389/neuro.01.024.2009 Pain modulation by nitric oxide in the spinal cord Marco Aurélio M. Freire1*, Joanilson S. Guimarães1,Walace Gomes Leal 2 and Antonio Pereira1,3* 1 Edmond and Lily Safra International Institute of Neuroscience of Natal (ELS-IINN), Natal, RN, Brazil 2 Federal University of Pará, Belém, PA, Brazil 3 Federal University of Rio Grande do Norte, Natal, RN, Brazil Nitric oxide (NO) is a versatile messenger molecule ﬁrst associated with endothelial relaxing effects. In the central nervous system (CNS), NO synthesis is primarily triggered by activation of N-methyl-D-aspartate (NMDA) receptors and has a Janus face, with both beneﬁcial and harmful properties. There are three isoforms of the NO synthesizing enzyme nitric oxide synthase (NOS): neuronal (nNOS), endothelial (eNOS), and inducible nitric oxide synthase (iNOS), each one involved with speciﬁc events in the brain. In the CNS, nNOS is involved with modulation of synaptic transmission through long-term potentiation in several regions, including nociceptive circuits in the spinal cord. Here, we review the role played by NO on central pain sensitization. Keywords: nitric oxide, interneuron, spinal cord, hyperalgesia, pain INTRODUCTION Nitric oxide (NO) is one of the most intriguing molecules to be found in the brain. This versa- tile neuronal messenger was ﬁrst identiﬁed as an endothelium-derived relaxing factor (EDRF), responsible for smooth muscle relaxation (Ignarro et al., 1987; Palmer et al., 1987). NO is freely dif- fusible across cell membranes and is synthesized by a group of enzymes, known as nitric oxide synthases (NOS), from L-arginine and different cofactors, depending on the cell type (Hobbs and Ignarro, 1996; Lipton et al., 1994; Marletta et al., 1998). Three members of the NOS family of enzymes have been identiﬁed in mammals: neu- ronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS), which have distinct func- tional and structural features (see Stuehr et al., 2004). Both nNOS (also known as Type I) and eNOS (Type III) activities are controlled by Ca2+- calmodulin and are expressed constitutively in the brain (Alderton et al., 2001); iNOS (Type II), on the other hand, once expressed is always active, being independent of intracellular Ca2+ levels (Stuehr and Grifﬁth, 1992), and is expressed in response to inﬂammatory and proinﬂammatory mediators acting on macrophages, astrocytes and microglia (Marletta, 1994). Though traditionally only nNOS has been associated with nitrergic sign- aling in the brain, there have been many evidences showing that eNOS also contributes to the physi- ological actions of NO in the brain parenchyma (Garthwaite, 2008). NO is very stable in low, physi- ological concentrations (Garthwaite, 2008) and is produced stoichiometrically after the conversion of L-arginine to citrulline in a process requiring both NADPH and O2 as co-substrates, and other cofactors (Marletta, 1993; Moncada et al., 1989; Vincent, 1994) (Figure 1). It is useful to divide the chemical reactions in which NO takes part as either direct or indirect (Wink et al., 2000). Direct reactions occur between low concentrations of NO and iron-containing proteins, such as gua- nylate cyclase (GC), and is responsible for most physiological actions of NO (Wink et al., 2000). Indirect reactions, conversely, occur when high concentrations of NO are present and generate Frontiers in Neuroscience www.frontiersin.org September 2009 | Volume 3 | Issue 2 | 175