Freire et al. LTP Long-lasting increase in synaptic efﬁciency following high-frequency stimulation of presynaptic elements. It was discovered in the hippocampus and depends on either N-methyl-D- aspartate (NMDA) receptor-dependent or -independent mechanisms to be evoked and on gene expression and protein synthesis to be maintained. Hyperalgesia Heightened sensitivity to pain caused by injury to peripheral tissues or neural elements. It can be elicited by both peripheral and central sensitization mechanisms. Peripheral mechanisms are triggered by inﬂammatory agents and the release of intracellular molecules by damaged cells. Central sensitization can be of the early and late-onset types. Early-onset sensitization is caused by LTP-like mechanisms, while the late-onset type involves changes in gene expression. rons located in superﬁcial laminae, using neuro- transmitters such as glutamate, that can directly activate them, and the neuropeptides substance P (SP) and neurokinin A (NKA), which modulate neuronal output in more subtle ways. Both SP and NKA are expressed through the preprotachykinin A (PPT-A) gene and bind to the neurokinin-1 (NK-1) receptor (Todd et al., 2002). Most of the spinal cord neurons in lamina I that possess the NK-1 receptor belong to the spinothalamic and spinoparabrachial tracts, that send ascending nociceptive information to the brain. When subjected to a regime of repetitive stim- ulation resulting from persistent tissue injury, nerve damage or electrical stimulation, spinal cord circuits are reorganized and pain is exacer- bated in a process called nociceptive sensitization (Wall and Woolf, 1984; Woolf, 1983). Nociceptive sensitization is perceived as a decreased thresh- old to both noxious and innocuous stimulation, called hyperalgesia and allodynia, respectively. This effect has the obvious adaptive value of forcing the animal to protect the injured site and avoid further damage. Nociceptive sensitization has both central and peripheral components. Peripheral sensitization results from the release of inﬂammatory mediators such as prostaglan- din E2 (PGE2), bradykinin, nerve growth factor (NGF), and NO in the injured site (Milligan and Watkins, 2009). These chemicals increase the sensitivity/excitability of sensory terminals leading to localized tissue effects. Central sensi- tization, on the other hand, can result from the repetitive activation of C-ﬁbers and the conse- quent temporal summation of dorsal horn neu- ronal responses, termed “windup” (Mendell and Wall, 1964). This sensitization operates on mech- anisms that are broadly similar to those underly- ing long-term potentiation (LTP) (see Ji et al., 2003 for a review). As with LTP in the hippocam- pus, activity-dependent plastic modiﬁcation of synapses between SP peripheral nociceptor ter- minals and lamina dorsal horn neurons occurs through phosphorylation of both α-amino-3- hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl-D-aspartate (NMDA) ionotropic receptors and the recruitment of AMPA receptors to the postsynaptic membrane (Ji et al., 2003) (Figure 2). The complement of second messenger pathways recruited in each case is slightly different (Ji et al., 2003). Though there is still much debate about speciﬁc details of the mechanisms involved, it seems evident that NO plays an important role as a signaling molecule on LTP in the hippocampus and other cortical areas (Haghikia et al., 2007; Hopper and Garthwaite, 2006). Nitric oxide and pain LTP mediated hyperalgesia occurs with the contribution of projection neurons in lamina I expressing the neurokinin 1 (NK ) receptor 1 (Ikeda et al., 2006). The presence of NO is essential for induction of LTP in lamina I neu- rons (Ikeda et al., 2006). In rats, the main source of NO in lamina I neurons are interneurons located in laminae II and III (Ruscheweyh et al., 2006). Recently, a study using some speciﬁc inhibitors for distinct NOS isoforms (Tanabe et al., 2009) showed that both nNOS and iNOS are involved with hyperalgesia. However, while nNOS has a deﬁnite role in spinal cord circuits, there is some disagreement whether iNOS also participates in central transmission (Tanabe et al., 2009) or it expressed only peripherally (De Alba et al., 2006) in both inﬂammatory and neuropathic pain models. Strong noxious stimuli lead to the activation of downstream serine/threonine protein kinases, including cAMP-dependent protein kinase (PKA), Ca+2/ phospholipid-dependent protein kinase (PKC), Ca+2/calmodulin-dependent protein kinase II (CaMKII), and (cGMP)-dependent protein kinase (PKG) (Ji et al., 2003; Tanabe et al., 2009; Wu et al., 2005), some of which with an effective participation of NO. Brieﬂy, the general mechanism by which NO participates in spinal nociceptive processing consists in the activation of soluble GC, which in turn generates cGMP. Intracellular elevation of the cGMP levels may further activate PKG (see Figure 2). Otherwise, NO may produce peroxynitrite by rapidly reacting with superoxide (Beckman et al., 1990), whose importance in enhancing phosphorylation of NMDA receptors, and consequently central sen- sitization, has been recently suggested in animal models of neuropathic and inﬂammatory pain (Gao et al., 2007). Besides, the ROS produced by either NO or NMDA-receptor activation, superoxide and peroxynitrite, respectively, also contribute to maintenance of hyperalgesia (Tanabe et al., 2009), and can stimulate directly the pheripheral nociceptive terminals (Aley et al., 1998). The crucial involvement of the NO-GC signaling pathway in inﬂammatory and neu- ropathic pain is underscored by the markedly reduced nociceptive behavior presented by a NO-GC knock-out mouse strain (Schmidtko et al., 2008). Inhibitors of NOS activity have also provided evidence for the role of NO in pain sensitization. Yonehara and coworkers (1997), in a chronic inﬂammatory pain model, reported a decrease in hyperalgesia after the intravenous administration of the arginine analog N-omega- nitro-L-arginine methyl ester (L-NAME), which Frontiers in Neuroscience www.frontiersin.org September 2009 | Volume 3 | Issue 2 | 178