Litwack Nitric Oxide

1. Auflage 2014
ISBN: 978-0-12-800439-5
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 96, 454 Seiten

Reihe: Vitamins and Hormones

First published in 1943, Vitamins and Hormones is the longest-running serial published by Academic Press. The Series provides up-to-date information on vitamin and hormone research spanning data from molecular biology to the clinic. A volume can focus on a single molecule or on a disease that is related to vitamins or hormones.  A hormone is interpreted broadly so that related substances, such as transmitters, cytokines, growth factors and others can be reviewed. This volume focuses on nitric oxide. - Expertise of the contributors - Coverage of a vast array of subjects - In depth current information at the molecular to the clinical levels - Three-dimensional structures in color - Elaborate signaling pathways

Autoren/Hrsg.

Litwack, Gerald

Inhaltsverzeichnis

1;Front Cover;1
2;Nitric Oxide;4
3;Copyright;5
4;Former Editors;6
5;Contents;8
6;Contributors;14
7;Preface;18
8;Chapter One: Regulation of Nociceptive Transduction and Transmission by Nitric Oxide;20
8.1;1. Introduction;21
8.2;2. Role of NO in Nociceptive Transduction at the Periphery;22
8.3;3. Diverse Effects of NO on Ion Channels Expressed on Primary Sensory Neurons;24
8.3.1;3.1. Acid-sensing ion channels;24
8.3.2;3.2. Transient receptor potential channels;24
8.3.2.1;3.2.1. TRPV1;24
8.3.2.2;3.2.2. TRPA1;25
8.3.2.3;3.2.3. TRPV3 and TRPV4;25
8.3.3;3.3. KATP channels;26
8.4;4. Role of NO in Regulating Nociceptive Transmission at the Spinal Cord Level;26
8.5;5. NO Reduces Excitatory, But Potentiates Inhibitory, Synaptic Transmission in Spinal Cords;28
8.5.1;5.1. Glutamatergic input from primary afferent nerves;29
8.5.2;5.2. Voltage-activated calcium channels in sensory neurons;30
8.5.3;5.3. Synaptic NMDA receptors;30
8.5.4;5.4. Synaptic release of glycine;30
8.6;6. Conclusions and Future Directions;31
8.7;Acknowledgments;33
8.8;References;33
9;Chapter Two: microRNA and Human Inducible Nitric Oxide Synthase;38
9.1;1. Introduction;38
9.2;2. Regulation of Human iNOS Gene;39
9.2.1;2.1. Transcriptional;39
9.2.2;2.2. Posttranscriptional;40
9.3;3. miRNAs Regulation;40
9.3.1;3.1. miR-939;41
9.3.2;3.2. other miRNAs;42
9.4;4. Conclusion;44
9.5;References;44
10;Chapter Three: Heart Mitochondrial Nitric Oxide Synthase: A Strategic Enzyme in the Regulation of Cellular Bioenergetics;48
10.1;1. Introduction;49
10.2;2. Heart Mitochondrial NO Production;50
10.2.1;2.1. Heart mtNOS activity;51
10.2.2;2.2. Heart mtNOS identity;53
10.3;3. Regulation of Heart mtNOS;55
10.3.1;3.1. Effect of substrates and cofactors;55
10.3.2;3.2. Effect of mitochondrial metabolic state and membrane potential;57
10.4;4. Effects of NO on Heart Mitochondrial Function;58
10.4.1;4.1. Nitric oxide consumption reactions in mitochondria;59
10.4.2;4.2. Regulation of mitochondrial function by NO;60
10.4.3;4.3. Mitochondrial NOS functional activity;63
10.5;5. Physiopathological Regulation of Heart mtNOS;66
10.5.1;5.1. Heart chronic hypoxia;66
10.5.2;5.2. Heart acute hypoxia and ischemia-reperfusion;67
10.6;6. Conclusions and Future Directions;69
10.7;Acknowledgments;70
10.8;References;70
11;Chapter Four: Nitric Oxide Regulation of Adult Neurogenesis;78
11.1;1. Introduction;78
11.2;2. Adult Neurogenesis;79
11.3;3. Expression of NOS in Neurogenic Regions;81
11.4;4. Pharmacological Studies of NO on Adult Neurogenesis In Vivo;82
11.5;5. NOS Knockout Animals and Adult Neurogenesis;83
11.6;6. Neuropeptide Y and NO;84
11.7;7. The Dual Role of NO in Adult Neurogenesis;86
11.8;8. Concentration-Dependent Effects of NO;89
11.9;9. Conclusions;91
11.10;References;91
12;Chapter Five: Nitric Oxide in the Nervous System: Biochemical, Developmental, and Neurobiological Aspects;98
12.1;1. Introduction;99
12.1.1;1.1. Brief history and biochemistry of NOS;99
12.1.2;1.2. NO classical actions;102
12.1.3;1.3. Interesting partners in the CNS: Focusing on NMDA receptors;104
12.2;2. NO Signaling Pathways;107
12.2.1;2.1. PKG modulation by NO;107
12.2.2;2.2. AKT modulation by NO;108
12.2.3;2.3. ERK1/2 modulation by NO;110
12.2.4;2.4. Src modulation by NO;110
12.2.5;2.5. CREB modulation by NO;111
12.3;3. NO and Neuronal Viability;112
12.4;4. NO and Neurotransmitters Release;117
12.4.1;4.1. Glutamate release;117
12.4.2;4.2. GABA release;119
12.4.3;4.3. DA release;120
12.4.4;4.4. 5-Hydroxytryptamine release;121
12.5;5. NO and Neuroplasticity;122
12.5.1;5.1. NO and structural plasticity;122
12.5.2;5.2. NO and functional plasticity;127
12.6;References;130
12.7;Further Reading;144
13;Chapter Six: Hippocampus and Nitric Oxide;146
13.1;1. Introduction;147
13.2;2. Profiles of NO in the CNS;149
13.2.1;2.1. NO formation;149
13.2.2;2.2. NO diffusion;150
13.2.3;2.3. NO metabolism;150
13.2.4;2.4. NO signaling;151
13.3;3. NO and Hippocampal Plasticity;153
13.3.1;3.1. NO and LTP;153
13.3.2;3.2. NO and neurogenesis;155
13.3.3;3.3. NO and synaptogenesis;158
13.4;4. NO and the Related CNS Disorders;161
13.4.1;4.1. NO and ischemia;161
13.4.2;4.2. NO and mood disorders;164
13.4.3;4.3. NO and Alzheimer´s disease;166
13.5;5. Conclusion;168
13.6;References;169
13.7;Further Reading;179
14;Chapter Seven: Nitric Oxide and Hypoxia Signaling;180
14.1;1. Introduction;181
14.1.1;1.1. Vignette-Tibetan highlanders and genetic evolution at the HIF genomic loci;182
14.2;2. Part 1: NO Biology in Normoxia, Hypoxia, and Anemia;183
14.2.1;2.1. NO biology, S-nitrosylation, and equilibrium of S-nitrosylated products (Fig.7.1);184
14.2.2;2.2. SNO products and physiology;185
14.2.3;2.3. HIF protein stabilization in hypoxia;186
14.2.4;2.4. S-Nitrosylation and the HIF pathway;189
14.2.5;2.5. NO inhibits HIF stabilization in hypoxia;190
14.2.6;2.6. Divergent roles of nNOS in hypoxia versus anemia;190
14.2.7;2.7. Physiological responses to anemia-Role of NO;194
14.2.7.1;2.7.1. Cardiovascular adaptation;194
14.2.7.2;2.7.2. Respiratory adaptation;195
14.2.7.3;2.7.3. Metabolic adaptation;195
14.2.7.4;2.7.4. Increased tissue oxygen extraction during anemia;196
14.3;3. Part 2: Effects of Hypoxia on NOSs;196
14.3.1;3.1. Neuronal NOS;196
14.3.2;3.2. Inducible NOS;198
14.3.3;3.3. Endothelial NOS;199
14.3.3.1;3.3.1. Regulation of eNOS transcription in hypoxia;199
14.3.3.2;3.3.2. Posttranscription regulation of eNOS in hypoxia;201
14.3.4;3.4. eNOS regulation in in vivo models of hypoxia;201
14.3.5;3.5. O2 dependency of NOS enzymes;203
14.4;4. Summary;204
14.5;References;204
14.6;Further Reading;211
15;Chapter Eight: NO Binding to the Proapoptotic Cytochrome c-Cardiolipin Complex;212
15.1;1. Introduction;213
15.2;2. The cyt c-CL Complex;214
15.3;3. Ligand Binding to the cyt c/CL Complex;216
15.3.1;3.1. NO binding to cyt c/CL complex;217
15.3.2;3.2. NO binding to the proximal side of heme: Insights from cyt c and sGC;220
15.4;4. Insights into the Nature and Formation of the Proximal NO Complex in cyt c-CL;222
15.5;5. Conclusions;224
15.6;References;225
16;Chapter Nine: The Nitric Oxide-Mediated Regulation of Prostaglandin Signaling in Medicine;230
16.1;1. Introduction;231
16.2;2. NOS and NO Production;232
16.2.1;2.1. Different redox species of NO;232
16.2.2;2.2. NO-mediated chemical reaction in biology;233
16.2.2.1;2.2.1. S-nitrosylation;234
16.2.2.2;2.2.2. Peroxynitrite-mediated reaction;236
16.3;3. COX and Prostaglandin in Biology;237
16.3.1;3.1. COX1 and -2;237
16.3.2;3.2. Function of prostaglandin signaling in biology;241
16.3.2.1;3.2.1. Nervous system;242
16.3.2.2;3.2.2. Cancer;243
16.3.2.3;3.2.3. Cardiovascular;244
16.3.2.4;3.2.4. Thermogenesis and metabolism;245
16.3.2.5;3.2.5. Bone metabolism and fracture healing;245
16.4;4. The Role of Nitric Oxide in Prostaglandin Regulation;247
16.4.1;4.1. Peroxynitrite-mediated regulation of prostaglandin synthesis;249
16.4.2;4.2. S-nitrosylation of COX;252
16.5;5. Perspective/conclusion;253
16.6;References;254
17;Chapter Ten: Nitric Oxide as a Mediator of Estrogen Effects in Osteocytes;266
17.1;1. Introduction;267
17.2;2. Bone-Protective Effects of Estrogen;268
17.3;3. Induction of NO Synthesis by Estrogen;269
17.4;4. NO/cGMP Signaling in Bone Cells;270
17.5;5. Bone-Anabolic Effects of NO in Humans-Lessons from Clinical Trials;272
17.6;6. Estrogen Promotion of Osteocyte Survival via the NO/cGMP/PKG Pathway;273
17.6.1;6.1. Antiapoptotic effects of estrogen in osteocytes and osteoblasts require NO/cGMP/PKG signaling;274
17.6.2;6.2. PKG Ia and PKG II are independently necessary for estradiol- and cGMP-mediated protection from apoptosis;275
17.6.3;6.3. Estradiol-induced Akt and Erk activation in osteocytes is mediated by NO/cGMP/PKG II and necessary for the hormone´s...;276
17.6.4;6.4. Antiapoptotic effects of estradiol and cGMP require BAD phosphorylation;276
17.7;Acknowledgment;278
17.8;References;278
18;Chapter Eleven: Insights into the Diverse Effects of Nitric Oxide on Tumor Biology;284
18.1;1. Introduction;285
18.2;2. Cellular Reactions of NO;286
18.2.1;2.1. Nitric Oxide and Cancer;293
18.2.2;2.2. NO and cancer etiology;294
18.2.3;2.3. NO and cancer progression;296
18.2.3.1;2.3.1. NOS and cancer;297
18.2.3.2;2.3.2. Angiogenesis;299
18.2.3.3;2.3.3. Epithelial-mesenchymal transition and metastasis;300
18.2.3.4;2.3.4. Epigenetics;303
18.2.4;2.4. NO and cancer treatments;306
18.3;3. Conclusion/Discussion;307
18.4;References;308
19;Chapter Twelve: Dual Effect of Interferon (IFN.)-Induced Nitric Oxide on Tumorigenesis and Intracellular Bacteria;318
19.1;1. Introduction;319
19.2;2. Interferon .;320
19.3;3. NOS2/NO;322
19.4;4. l-Arg Metabolism;324
19.4.1;4.1. Arginase;324
19.4.2;4.2. NOS/NO;325
19.5;5. NOS2/NO in Disease;326
19.5.1;5.1. Bacterial pathogens;326
19.5.2;5.2. Cancer;327
19.6;6. IFN.-Induced NO as a Mechanism to Inhibit Renal Cancer Growth;329
19.7;7. Conclusions and Future Directions;334
19.8;Acknowledgments;335
19.9;References;335
20;Chapter Thirteen: Antiobesogenic Role of Endothelial Nitric Oxide Synthase;342
20.1;1. Introduction;342
20.2;2. eNOS is Important for Regulating Vascular and Metabolic Function;344
20.3;3. NO Bioavailability is Decreased in Obese and Diabetic States;345
20.4;4. Regulation of Obesity and Insulin Resistance by eNOS;349
20.5;5. Synopsis;353
20.6;Acknowledgments;354
20.7;References;354
21;Chapter Fourteen: Nitric Oxide and Cerebrovascular Regulation;366
21.1;1. Introduction;367
21.2;2. Sources of NO in the Neurovascular Unit;368
21.3;3. Resting CBF;369
21.3.1;3.1. Studies in transgenic mice;373
21.3.2;3.2. Vasomotion;374
21.3.3;3.3. Shear stress;375
21.4;4. Autoregulation;377
21.4.1;4.1. Lower limit;377
21.4.2;4.2. Upper limit;378
21.4.3;4.3. Dynamic autoregulation;379
21.5;5. Neurovascular Coupling (Fig.14.1);379
21.5.1;5.1. Sources of NO involved in NVC;382
21.5.2;5.2. NO and NVC in the cerebellum;388
21.5.3;5.3. Permissive or obligatory role of NO;389
21.6;6. Conclusion;389
21.7;Acknowledgments;390
21.8;References;390
22;Chapter Fifteen: Endothelial Nitric Oxide Synthase Gene Polymorphisms in Cardiovascular Disease;406
22.1;1. Introduction;407
22.2;2. Genetic Variants;408
22.2.1;2.1. The Glu298Asp variant;410
22.2.2;2.2. The -786T/C variant;410
22.2.3;2.3. Intron 4 VNTR variant;410
22.3;3. eNOS Polymorphisms in CVD;411
22.3.1;3.1. Coronary artery disease and myocardial infarction;411
22.3.2;3.2. Hypertension;413
22.3.3;3.3. Pre-eclampsia;415
22.3.4;3.4. Ischemic stroke;415
22.3.5;3.5. Other CVDs;416
22.4;4. eNOS Polymorphisms in Other Diseases;417
22.4.1;4.1. Metabolic disorders;417
22.4.2;4.2. Cancer;418
22.4.3;4.3. Systemic lupus erythematosus;419
22.4.4;4.4. Migraine;419
22.5;5. Conclusion;419
22.6;References;420
23;Chapter Sixteen: Role of Nitric Oxide in Pathophysiology and Treatment of Pulmonary Hypertension;426
23.1;1. Role of NO in Vasorelaxation and Proliferation in PH;427
23.2;2. Endothelial Nitric Oxide Synthase Expression and its Activity in Relationship to the Vasoreactivity;429
23.2.1;2.1. eNOS uncoupling;429
23.2.2;2.2. Caveolin-1 and eNOS uncoupling;430
23.2.3;2.3. Bone morphogenetic protein receptor type II and eNOS;430
23.2.4;2.4. Vascular endothelial growth factor and eNOS expression;431
23.3;3. Physiological Role of NO in Pulmonary Hypertension;431
23.3.1;3.1. Role of NO in vascular basal tone;431
23.3.2;3.2. Vasoreactivity to NO-related vasorelaxants in rat lung;432
23.3.2.1;3.2.1. Physiological changes in rats with hypoxic PH;432
23.3.2.2;3.2.2. Physiological changes in rats with MCT-induced PH;432
23.3.2.3;3.2.3. Experimental studies focusing on NO inhalation in PH;433
23.4;4. Use of NO in Patients with PH in Clinical Practice;433
23.4.1;4.1. NO-related relaxation responses in patients with pulmonary hypertension;433
23.4.2;4.2. NO delivery in clinical use (NO donors and NO inhalation);434
23.4.3;4.3. Physiological effect of NO inhalation;434
23.4.4;4.4. Effects of inhaled NO on PAP;434
23.4.5;4.5. Effects of inhaled NO on arterial oxygenation;435
23.5;5. Clinical Application of NO Inhalation in Patients with Pulmonary Hypertension;435
23.5.1;5.1. Persistent pulmonary hypertension of the neonate;435
23.5.2;5.2. Bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome;436
23.5.3;5.3. Pulmonary hypertensive crisis after cardiac surgery of congenital heart defect;437
23.5.4;5.4. Acute lung injury and/or adult respiratory distress syndrome;437
23.5.5;5.5. Chronic obstructive pulmonary disease;437
23.5.6;5.6. Other findings and future directions;438
23.6;References;438
24;Index;444
25;Color Plate;456

Leseproben

Chapter One Regulation of Nociceptive Transduction and Transmission by Nitric Oxide
Alexis Bavencoffe; Shao-Rui Chen; Hui-Lin Pan1    Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
1 Corresponding author: email address: [e-mail] Abstract
The potential involvement of nitric oxide (NO), a diffusible gaseous signaling messenger, in nociceptive transduction and transmission has been extensively investigated. However, there is no consistent and convincing evidence supporting the pronociceptive action of NO at the physiological concentration, and the discrepancies are possibly due to the nonspecificity of nitric oxide synthase inhibitors and different concentrations of NO donors used in various studies. At the spinal cord level, NO predominantly reduces synaptic transmission by inhibiting the activity of NMDA receptors and glutamate release from primary afferent terminals through S-nitrosylation of voltage-activated calcium channels. NO also promotes synaptic glycine release from inhibitory interneurons through the cyclic guanosine monophosphate/protein kinase G signaling pathway. Thus, NO probably functions as a negative feedback regulator to reduce nociceptive transmission in the spinal dorsal horn during painful conditions. Keywords Nitric oxide synthase Neuron Neurotransmitter Nociceptor Pain Spinal cord Synaptic transmission 1 Introduction
Pain receptors, also called nociceptors, are a group of sensory neurons with specialized nerve endings widely distributed in the skin, deep tissues (including the muscles and joints), and most of visceral organs. They respond to tissue injury or potentially damaging stimuli by sending nerve signals to the spinal cord and brain to begin the process of pain sensation. Nociceptors are equipped with specific molecular sensors, which detect extreme heat or cold and certain harmful chemicals. Mechanical nociceptors can also respond to tissue-damaging stimuli, such as pinching the skin or over-stretching the muscles. Activation of nociceptors generates action potentials, which are propagated along the afferent nerve axons, especially unmyelinated C-fibers and thinly myelinated Ad-fibers. At the spinal cord level, the nociceptive nerve terminals release excitatory neurotransmitters to activate their respective postsynaptic receptors on second-order neurons. In the spinal dorsal horn, both excitatory and inhibitory interneurons can augment or attenuate nociceptive transmission (Cervero & Iggo, 1980; Zhou, Zhang, Chen, & Pan, 2007, 2008). The nociceptive signal, encoding the quality, location, and intensity of the noxious stimuli, is then conveyed via the ascending pathway to reach various brain regions to elicit pain sensation. Physiological pain responses normally protect us from tissue damage by quickly alerting us to impending injury. Unlike acute physiological pain, chronic pathological pain, including neuropathic and inflammatory pain, is often associated with increased activity and responses of spinal dorsal horn neurons, termed central sensitization (Woolf & Thompson, 1991; Xu, Dalsgaard, & Wiesenfeld-Hallin, 1992). This phenomenon is the cellular basis for hyperalgesia (increased pain response to a noxious stimulus) and allodynia (painful sensation in response to a nonnoxious stimulus). Nitric oxide (NO) is a membrane-permeable gaseous second messenger involved in signal transduction. The physiological function of NO has been shown in a large variety of cell types and tissues, including the immune system, blood vessels, endothelial cells, and neurons. NO is produced from L-arginine by three major isoforms of nitric oxide synthase (NOS): neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3) (Alderton, Cooper, & Knowles, 2001; Knowles & Moncada, 1994). Both nNOS and eNOS are constitutively expressed and activated by Ca2 +/calmoduline-dependent signaling, whereas iNOS is typically induced by immunostimulation, such as inflammatory cytokines and bacterial endotoxins, independent of intracellular Ca2 + levels. Classically, the intracellular NO effect is mediated by the NO-sensitive soluble guanylyl cyclase (sGC). When activated, sGC converts guanosine triphosphates (GTP) into cyclic guanosine monophosphates (cGMP). cGMP has different targets such as serine/threonine protein kinases G (PKG-I and PKG-II), cGMP-regulated phosphodiesterase, and cGMP-activated ion channels (Ahern, Klyachko, & Jackson, 2002; Calabrese et al., 2007). In addition, NO can promote a covalent and reversible posttranslational protein modification by interacting with the thiol side chain of cysteine residues. This chemical reaction, named S-nitrosylation, occurs without the action of any enzymes (Ahern et al., 2002; Choi et al., 2000). The role of NO in pain signaling has been investigated in many studies using rodent models and in humans. In this chapter, we critically review the reported complex actions of NO in pain transduction and transmission. We also present recent electrophysiological evidence showing that NO inhibits nociceptive transmission at the spinal cord level and the signaling mechanisms involved. 2 Role of NO in Nociceptive Transduction at the Periphery
The evidence about the role of NO in pain transduction is inconsistent and conflicting. In human subjects, injection of the NO solution (> 0.7 mM) into the paravascular tissues and veins (Holthusen & Arndt, 1995) or the cutaneous tissue in the forearm (Holthusen & Arndt, 1994) evokes pain in a dose-dependent fashion. However, the physiological relevance of high NO concentrations used in these studies is not clear, because the tissue level of NO is < 10 µM (Wink et al., 1993). On the other hand, local infusion of the NO donor glyceryl trinitrate at the site of surgery produces a small analgesic effect in humans undergoing oral surgery (Hamza et al., 2010). Also, transdermal nitroglycerine alone does not affect pain itself but prolongs the analgesic effect of opioids in patients after knee surgery (Lauretti, de Oliveira, Reis, Mattos, & Pereira, 1999). Others have reported that inhaled NO can reduce pain intensity in patients with sickle cell crisis (Head et al., 2010) and that local spray of isosorbide dinitrate, an NO donor, reduces pain and burning sensation, in diabetic patients (Yuen, Baker, & Rayman, 2002). Nevertheless, the potential therapeutic effect of NO donors for chronic pain treatment still needs to be confirmed in large scale clinical trials. It has been reported that local injection of NG-methyl-L-arginine (L-NMA), an NOS inhibitor, attenuates mechanical hypersensitivity caused by injection of prostaglandin E2 into the rat skin (Chen & Levine, 1999). Also, systemic treatment with an NOS inhibitor, NG-nitro-K-arginine methyl ester (L-NAME), attenuates tactile and cold allodynia in a rat model of neuropathic pain induced by spinal nerve ligation (Yoon, Sung, & Chung, 1998). However, others have shown that the antiallodynic effect of L-NAME cannot be reversed by L-arginine (Lee, Singh, & Lodge, 2005). Furthermore, systemic treatment with other NOS inhibitors, including 7-nitroindazole, N(omega)-nitro-L-arginine (L-NNA), aminoguanidine, and LY457963, does not affect allodynia in rats subjected to spinal nerve ligation (Lee et al., 2005; Luo et al., 1999). Thus, it seems that the commonly used NOS inhibitors, such as L-NAME, may affect targets other than NOS. In support of this possibility, it has been demonstrated that the arginine analogues with alkyl or aryl esterification, including L-NAME, are in fact muscarinic receptor antagonists (Buxton et al., 1993; Chang, Chen, & Hsiue, 1997). In addition, tactile allodynia caused by nerve injury or tissue damage is attenuated in nNOS-knockout mice (Chu et al., 2005; Guan, Yaster, Raja, & Tao, 2007). sGC-knockout mice also show reduced nociceptive responses to tissue inflammation or nerve injury, but their responses to acute pain are not affected (Schmidtko et al., 2008). It should be acknowledged that in eNOS-, nNOS-, or iNOS-knockout mice, there is a developmental compensatory increase in the expression of other NOS isoforms in the spinal cord (Boettger et al., 2007; Tao et al., 2003). This compensatory upregulation of other NOS subtypes in specific NOS isoform-knockout mice complicates the interpretation of the behavioral test results. In contrast, it has been shown that local injection of an NO donor, sodium nitroprusside, reduces mechanical hyperalgesia in the rat paw induced by prostaglandin E2 injection (Durate, Lorenzetti, & Ferreira, 1990). Interestingly, topical application of a cream containing different concentrations of NO donors, S-nitroso-N-acetylpenicillamine (SNAP) or isosorbide dinitrate, produces an opposite effect on allodynia in a rat model of postoperative pain (Prado, Schiavon, & Cunha, 2002). At a low concentration, SNAP (1–10%) or isosorbide (2.5–5%) reduces allodynia through the guanylyl...