Freire et al. Nitric oxide and pain Figure 2 | Processing of pain information in the spinal cord. Pain signals are transmitted to the dorsal horn by nociceptive terminals that synapse with neurons located in laminae I, II, and III. Early-onset activity-dependent central sensitization of ascending pathways depends on LTP of the synapse between peripheral terminal containing substance P and spinothalamic projection neurons in lamina I. Pain sensitization depends, in some level, on nitric oxide (NO) released by interneurons located in laminae II and III and also by glial cells. Abbreviations: AMPAr: α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor; NMDAr: N-methyl-D-aspartate receptor; NK1r: neurokinin 1 receptor; Glu: glutamate; Ins(1,4,5)P3: Inositol 1,4,5-triphosphate; CaMKII: calcium/ calmodulin-dependent protein kinase II; PKA: protein kinase A; PKC: protein kinase C; PKG: protein kinase G; NOS: nitric oxide synthase; ERK: extracellular signal-regulated kinase; cGMP: cyclic guanosine monophosphate; IL-1β: interleukin 1beta;TNFα: tumor necrosis factor-alfa; ROS: reactive oxygen species. inhibits the nNOS and eNOS isoforms (Knowles and Moncada, 1994; Parkinson, 2000). More recently, however, other groups were also able to show the speciﬁc role of iNOS in hyperalge- sia by using highly selective inhibitors for this isoform, such as N-(3-[Aminomethyl] benzyl) acetamidine (1400W) (Tang et al., 2007) and (S)-2-amino-7-acetamidino-5-thioheptanoic acid (GW274150) (De Alba et al., 2006). Both inhibitors induced a signiﬁcant reduction in hyperalgesia. CONCLUSIONS Since its discovery in the 1980’s, NO has been shown to be a key player in many normal and pathological events in the brain. In normal condi- tions, it is produced in every major region of the CNS by a speciﬁc group of NADPH-d positive neurons. NO easily diffuses through cell mem- branes and gets to the intracellular compartment, where it increases the level of the second mes- senger cGMP (Qian et al., 1996) and initiates a cascade of molecular events leading to apoptosis, neurogenesis, LTP, etc. The NO-dependent LTP of nociceptive pathways in the spinal cord is a crucial mechanism behind long-term central pain sensitization. The ensuing hyperalgesia and allo- dynia warns the animal to the need to protect the affected region on the periphery. NO is released by interneurons in spinal cord’s laminae II and III and affects synapses between peripheral nocic- eptor terminals and lamina I neurons sending upward projections to the brain. The amount of NOS in this region is upregulated during sensi- tization and could be responsible for the main- tenance of LTP. ACKNOWLEDGMENTS Supported by grants CNPq 479936/2008-0, 481132/2007-4, and 304422/2006-1 to AP. The authors wish to thank Financiadora de Estudos e Projetos (FINEP), and Associação Alberto Santos Dumont para Apoio à Pesquisa (AASDAP) – Brazil. Frontiers in Neuroscience www.frontiersin.org September 2009 | Volume 3 | Issue 2 | 179