Abstract
A large body of evidence indicates that nitric oxide (NO) plays an important role in the processing of persistent inflammatory and neuropathic pain in the spinal cord. Several animal studies revealed that inhibition or knockout of NO synthesis ameliorates persistent pain. However, spinal delivery of NO donors caused dual pronociceptive and antinociceptive effects, pointing to multiple downstream signaling mechanisms of NO. This review summarizes the localization and function of NO-dependent signaling mechanisms in the spinal cord, taking account of the recent progress made in this field.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
1 Expression of NO Synthases in the Spinal Cord and in Dorsal Root Ganglia
Nitric oxide (NO) serves as a key biological signal in the regulation of many physiological and pathophysiological functions (Francis et al. 2010). It is a small gaseous molecule with a half-life of several seconds that readily permeates cell membranes. As NO cannot be stored in vesicles and secreted in a controlled fashion, its functions are primarily regulated by the expression and activity of NO synthases (NOSs) that produce NO and l-citrulline from the precursor l-arginine. Three different NOS isoforms have been identified that are encoded by three distinct genes. According to their primary origins or properties, NOS isoforms are referred to as neuronal NOS (nNOS or NOS-1), inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3). Both nNOS and eNOS are expressed constitutively, exhibit low basal activity, and are stimulated by Ca2+ influx and Ca2+/calmodulin binding. iNOS is induced in response to inflammatory stimuli, and its activity does not depend on intracellular Ca2+. The activities of NOS enzymes are regulated by several mechanisms, including phosphorylation, nitrosylation, interaction with other proteins, cofactor/substrate availability, and changes in transcription (Bian et al. 2006; Francis et al. 2010).
A large body of evidence indicates that nNOS is a major source of NO during pain processing in the dorsal horn of the spinal cord. Under basic conditions, nNOS is constitutively expressed in some neurons (5–18 % of total neurons) in laminae I–III (Valtschanoff et al. 1992; Dun et al. 1993; Spike et al. 1993; Zhang et al. 1993; Herdegen et al. 1994; Laing et al. 1994; Saito et al. 1994; Bernardi et al. 1995; Ruscheweyh et al. 2006; Sardella et al. 2011; Gassner et al. 2013). Double-labeling immunostaining experiments detected nNOS in a subpopulation of GABAergic inhibitory neurons which innervate giant projection neurons in lamina I (Puskar et al. 2001) and only sparsely overlap with other subpopulations of inhibitory neurons positive for neuropeptide Y, galanin, and parvalbumin (Laing et al. 1994; Tiong et al. 2011; Polgar et al. 2013). nNOS is also expressed at a relatively low level by excitatory interneurons positive for protein kinase Cγ in laminae II and III of the spinal cord (Hughes et al. 2008; Sardella et al. 2011) and in the somata of a few (<5 %) dorsal root ganglion (DRG) neurons (Aimi et al. 1991; Valtschanoff et al. 1992; Zhang et al. 1993; Henrich et al. 2002; Ruscheweyh et al. 2006).
With regard to the pain-relevant functions of NO, it is important to note that nNOS expression in the dorsal horn and in DRGs is considerably upregulated during the processing of persistent pain. Several animal studies demonstrated that the number of nNOS-immunoreactive dorsal horn neurons and the optical nNOS density in the dorsal horn are increased during inflammatory pain evoked by injection of proinflammatory agents such as formalin, zymosan, or complete Freund’s adjuvant into a hindpaw (Herdegen et al. 1994; Yonehara et al. 1997; Maihofner et al. 2000; Chu et al. 2005). In contrast, during neuropathic pain in response to peripheral nerve injury, nNOS expression was primarily upregulated in DRG neurons, leading to an increased number of nNOS-positive DRG neurons and enhanced nNOS immunoreactivity in their central terminals in the dorsal horn of the spinal cord (Zhang et al. 1993; Luo et al. 1999; Guan et al. 2007; Martucci et al. 2008). Hence, nNOS seems to play a particular role in the processing of persistent inflammatory and neuropathic pain in the spinal cord and is expressed in different neuronal populations.
Unlike nNOS, iNOS is, if at all, only weakly expressed in the dorsal horn and in DRGs under basic conditions (Wu et al. 1998; Maihofner et al. 2000; Henrich et al. 2002; Keilhoff et al. 2002; Chu et al. 2005; Ruscheweyh et al. 2006; Tang et al. 2007; Martucci et al. 2008). Data about iNOS induction in response to painful stimuli are not consistent. Whereas some studies reported iNOS induction in the spinal cord during the processing of inflammatory and/or neuropathic pain (Guhring et al. 2000; Tao et al. 2003; Martucci et al. 2008; Hervera et al. 2012), other studies reported that iNOS was not induced by painful stimuli (Keilhoff et al. 2002; Chu et al. 2005; De Alba et al. 2006; Guan et al. 2007). Moreover, the cellular distribution of iNOS in the spinal cord remains unclear. Finally, eNOS is constitutively expressed in vascular structures of the dorsal horn and DRGs (Keilhoff et al. 2002; Chu et al. 2005; Ruscheweyh et al. 2006), and its expression seems not to be regulated during pain processing (Keilhoff et al. 2002; Chu et al. 2005; Guan et al. 2007).
2 Pro- and Antinociceptive Functions of NO
The first evidence for a functional contribution of NO to pain processing was discovered in studies using NOS inhibitors such as l-NAME and l-NMMA, which inhibit all three NOS isoforms in a nonspecific manner. These early studies revealed that intrathecal (i.t.) administration of NOS inhibitors effectively ameliorated the pain behavior in various rodent models of inflammatory and neuropathic pain (for review, see Meller and Gebhart 1993; Luo and Cizkova 2000). Experiments with more selective NOS isoform inhibitors point to an important role of nNOS in the development and maintenance of inflammatory and neuropathic pain (Tao et al. 2004; Chu et al. 2005; Guan et al. 2007; Dableh and Henry 2011) and to a contribution of iNOS to the processing of inflammatory pain (Guhring et al. 2000; Tao et al. 2003).
In addition to NOS inhibitors, NOS isoform-specific knockout mice were used to investigate the pain-relevant functions of NO. Many of these studies revealed that persistent pain behaviors were moderately reduced in nNOS and iNOS but not in eNOS knockout mice. However, the interpretation of the pain behavior in mice lacking a NOS isoform is complicated by the fact that the expression of other NOS isoforms may be compensatory upregulated (Tao et al. 2003, 2004; Boettger et al. 2007; Hervera et al. 2010). Moreover, in the widely used nNOS knockout mouse line with targeted deletion of exon 2, alternatively spliced nNOS variants that are functionally active (such as nNOSβ) are still present in distinct tissues (Eliasson et al. 1997). These obstacles may account for the relatively modest pain phenotypes observed in mice lacking nNOS and/or iNOS (Guhring et al. 2000; Tao et al. 2003, 2004; Chu et al. 2005; Boettger et al. 2007; Guan et al. 2007; Hervera et al. 2010; Kuboyama et al. 2011; Keilhoff et al. 2013).
Because inhibition or knockout of NO synthesis ameliorated persistent pain, NO donors were expected to have mainly pronociceptive effects. Indeed, it has been observed that intrathecally administered NO donors may induce or increase hyperalgesia (Kitto et al. 1992; Meller et al. 1992; Machelska et al. 1998; Ferreira et al. 1999; Lin et al. 1999). However, other studies revealed that NO may also have antinociceptive properties within the spinal cord (Luo and Cizkova 2000). For example, i.t. administration of the NO precursor, l-arginine, reduced the activity of dorsal horn neurons and increased the mechanical threshold for tail withdrawal (Haley et al. 1992; Zhuo et al. 1993). Several studies suggested that the concentration of NO may be an important determinant to explain these dual pro- and antinociceptive effects. For example, neuropathic and postoperative pain behavior of rats was inhibited by administration of low doses of an NO donor, while it was further increased by high doses (Sousa and Prado 2001; Kina et al. 2005). Furthermore, dose-dependent dual NO effects have also been observed in humans: NO administration via a transdermal nitroglycerin patch reduced pain due to shoulder or elbow injury at low NO doses (Berrazueta et al. 1996; Paoloni et al. 2003) and enhanced opioid analgesia (Lauretti et al. 1999a, b). Conversely, high doses of transdermal nitroglycerin patches or ointment induced hyperalgesia (Lauretti et al. 1999a; Cadiou et al. 2007). Altogether, there is considerable evidence that inhibition of NO production in the spinal cord ameliorates persistent inflammatory and neuropathic pain. In contrast, delivery of NO donors may exert both pro- and antinociceptive effects, pointing to different downstream signaling pathways of NO action (Schmidtko et al. 2009).
3 Downstream Mechanisms of NO-Mediated Pain Processing
3.1 Activation of NO-GC
At nanomolar levels, NO binds to a prosthetic heme of NO-sensitive guanylyl cyclase (NO-GC; also referred to as soluble guanylyl cyclase, sGC) and causes the conversion of GTP to cGMP (Francis et al. 2010). NO-GC is a heterodimer consisting of two different subunits termed α and β. Two catalytically active isoforms have been identified (α1β1 and α2β1) in which the β1 subunit acts as the dimerizing partner for the α1 or α2 subunit (Friebe et al. 2007). There is considerable evidence that NO-GC is a major NO target during pain processing. Mice deficient for the β1 subunit (GC-KO mice), which are completely devoid of NO-GC activity, failed to develop pain sensitization induced by intrathecal administration of NO donors. GC-KO mice also demonstrated considerably reduced pain behaviors in inflammatory and neuropathic pain models, whereas the immediate responses to acute nociceptive stimuli were normal (Schmidtko et al. 2008a). The important role of NO-GC for persistent pain processing in the spinal cord is further supported by antinociceptive effects of the NO-GC inhibitor ODQ after intrathecal injection in models of inflammatory and neuropathic pain (Ferreira et al. 1999; Kawamata and Omote 1999; Tao and Johns 2002; Song et al. 2006). Moreover, similar to NO donors, both pronociceptive and antinociceptive effects were observed after i.t. administration of cGMP analogs (Garry et al. 1994; Iwamoto and Marion 1994; Ferreira et al. 1999; Song et al. 2006), and again the administered dose seems to be a determinant for this dual effect (Tegeder et al. 2002, 2004; Schmidtko et al. 2008b). Dual effects of NO and cGMP were also observed in electrophysiological studies with spinal cord slices, in which superfusion with both NO donors and cGMP analogs inhibited ~50 % but activated ~30 % of dorsal horn neurons (Pehl and Schmid 1997).
The most likely reason for the dual effects of NO donors and cGMP analogs is the presence of different pronociceptive and antinociceptive NO/cGMP downstream signaling mechanisms. Unlike the membrane-permeable gas NO, cGMP mainly acts in intracellular compartments at its site of production. Interestingly, the expression pattern of NO-GC in the spinal cord and in DRGs suggests that NO-mediated cGMP production can modulate pain processing at different sites. In the spinal cord, NO-GC immunoreactivity is enriched in inhibitory interneurons in laminae II and III, i.e., in the area of highest nNOS expression (see above). NO-GC is also expressed in neurokinin 1 (NK1) receptor-positive projection neurons in lamina I (Ding and Weinberg 2006; Ruscheweyh et al. 2006; Schmidtko et al. 2008a). These cells not only contribute to the ascending conduction of pain but are also essential for NO-dependent long-term potentiation (LTP) at the first synapse in pain pathways (Mantyh and Hunt 2004; Ikeda et al. 2006). In DRGs, however, specific NO-GC immunoreactivity was unexpectedly not detected in neurons. Instead thereof, NO-GC protein seems to be present only in satellite cells and vascular cells (Schmidtko et al. 2008a). This finding is supported by observations that axotomy of the sciatic nerve or incubation of DRG sections with an NO donor initiated cGMP production selectively in non-neuronal DRG cells (Morris et al. 1992; Shi et al. 1998). Considering that peripheral nerve injury leads to nNOS upregulation in somata of DRG neurons (see above) and that satellite cells contain NO-GC, it is likely that NO acts as a paracrine messenger from DRG neurons to satellite cells, thereby possibly contributing to the satellite cell proliferation in response to peripheral nerve injury (Zhuang et al. 2005; Scholz and Woolf 2007; Zhang et al. 2007; Kawasaki et al. 2008). Importantly, the observation that NO-GC is not expressed in primary afferent neurons challenges an earlier hypothesis that NO might act as “retrograde” transmitter which is released by spinal cord neurons and stimulates cGMP production via NO-GC activation in primary afferent neurons (Meller and Gebhart 1993; Luo and Cizkova 2000). Instead thereof, NO seems to be primarily a transmitter that (1) is released from nNOS-positive DRG neurons and dorsal horn interneurons (and possibly from so far unidentified iNOS-positive cells) and (2) induces cGMP production in DRG satellite cells, in lamina I projection neurons, and in laminae II/III inhibitory interneurons (Schmidtko et al. 2009).
3.2 cGMP Signaling
The elucidation of downstream mechanisms of NO/cGMP signaling in the nociceptive system has been complicated by at least two facts: First, cGMP in general signals by various mechanisms including activation of cGMP-dependent protein kinase (cGK; also referred to as protein kinase G, PKG), activation of cyclic-nucleotide-gated (CNG) channels, modulation of hyperpolarization-activated and cyclic-nucleotide-gated (HCN) channels, and modulation of phosphodiesterases (PDEs) (Craven and Zagotta 2006; Feil and Kleppisch 2008). Recent data indicate that all these cGMP targets are present in the nociceptive system. Second, cGMP is produced not only by NO-GC but also in a NO-independent manner by particulate guanylyl cyclases in response to stimulation by natriuretic peptides. Seven particulate guanylyl cyclase isoforms activated by different ligands have been identified in rodents (Garbers et al. 2006), and particulate guanylyl cyclases A and B (GC-A and GC-B; also referred to as natriuretic peptide receptor A [NPR-A] and natriuretic peptide receptor B [NPR-B], respectively) have been detected in DRG neurons (Schmidt et al. 2007; Kishimoto et al. 2008; Schmidtko et al. 2008a; Zhang et al. 2010; Loo et al. 2012).
After the discovery of pain-relevant NO/cGMP signaling in the 1990s, it was initially thought that most effects of NO and cGMP are mediated by cGKI (Qian et al. 1996), corresponding to the functional NO/NO-GC/cGMP/cGKI signaling pathway that exists in many other tissues (Feil and Kleppisch 2008). More recent studies confirmed the important pain-relevant role of cGKI, but cGKI seems to be mainly activated by NO-independent mechanisms during pain processing (see below). Several immunohistochemical studies detected the α-isoform of cGKI in the majority of DRG neurons and their nerve terminals in the spinal cord and in some dorsal horn neurons (Qian et al. 1996; Tao et al. 2000; Sung et al. 2006; Schmidtko et al. 2008b; Luo et al. 2012; Lorenz et al. 2014). After peripheral nerve injury and inflammation, cGKIα is activated in DRG neurons (Sung et al. 2004, 2006; Lorenz et al. 2014), and its expression increases in the spinal cord (Tao et al. 2000; Tegeder et al. 2002; Schmidtko et al. 2003). The essential contribution of cGKIα to persistent pain processing is reflected by the reduced inflammatory and/or neuropathic pain behavior in global or nociceptor-specific cGKI mutants (Tegeder et al. 2004; Luo et al. 2012; Lorenz et al. 2014) and by profound antinociceptive effects of intrathecally administered cGKI inhibitors (Tao et al. 2000; Schmidtko et al. 2003, 2009; Luo et al. 2012; Lorenz et al. 2014). So far identified targets that are phosphorylated by cGKIα in DRG neurons include cysteine-rich protein 4 (CRP4; initially named CRP2, Schmidtko et al. 2008b), vasodilator-stimulated phosphoprotein (VASP), myosin light chains (MLC), inositol 1,4,5-triphosphate receptor 1 (IP3R1) (Luo et al. 2012), and possibly large-conductance Ca2+-activated K+ channels (BKCa) (Zhang et al. 2010; Lu et al. 2014).
However, consistent with the cellular distribution of cGKIα and NO-GC described above, double-immunohistochemical stainings confirmed that cGKI and NO-GC are not colocalized in DRGs and only partially colocalized in the spinal cord (Schmidtko et al. 2008a). This implicates that upstream mechanisms different from NO and NO-GC may activate cGKIα during pain processing. Indeed, several studies demonstrated that the particulate guanylyl cyclases GC-A and GC-B are colocalized with cGKIα in DRG neurons and mediate cGKIα activation after stimulation with natriuretic peptides (Schmidt et al. 2007; Kishimoto et al. 2008; Schmidtko et al. 2008a; Zhang et al. 2010). In addition, an alternate mechanism of cGMP-independent cGKIα activation has been recently discovered in DRG neurons: Oxidants such as hydrogen peroxide (H2O2) can cause interprotein disulfide bond formation between two cGKIα cysteine residues, rendering the kinase catalytically active, independently of cGMP (Burgoyne et al. 2007). Interestingly, H2O2-induced cGKIα disulfide bond formation was increased in DRGs after peripheral nerve injury, and knock-in mice with impaired H2O2 activation but normal cGMP activation of cGKIα demonstrated reduced neuropathic pain behaviors (Lorenz et al. 2014). Hence, both cGMP derived from particulate guanylyl cyclases and H2O2 derived from so far unidentified sources activate cGKIα in DRGs during pain processing. In contrast, NO and NO-GC seem to use targets different from cGKIα to mediate their pain-relevant effects in DRGs.
In a recent study, CNG channels were identified as a novel target of NO signaling during pain processing: Using in situ hybridization experiments, the CNG channel subunit CNGA3 was detected in inhibitory neurons of the dorsal horn and in DRG satellite cells. After hindpaw inflammation, CNGA3 expression was upregulated in the dorsal horn and in DRGs, and mice lacking CNGA3 (CNGA3−/−) showed increased inflammatory pain behaviors. Moreover, the pain hypersensitivity evoked by i.t. delivery of cGMP analogs and NO donors was increased in CNGA3−/− mice (Heine et al. 2011), indicating that CNGA3-positive CNG channels are a downstream target of NO signaling that contributes in an inhibitory manner to persistent pain processing. Further studies are required to identify additional downstream targets that mediate the pro- and antinociceptive effects of NO-mediated cGMP production.
3.3 S-Nitrosylation
A cGMP-independent mechanism of NO signaling is S-nitrosylation, i.e., the covalent and reversible attachment of NO to a reactive cysteine thiol (Hess et al. 2005). Several recent in vitro and ex vivo studies indicate that S-nitrosylation is a signaling mechanism of NO during pain processing (for review, see Tegeder et al. 2011). For example, whole-cell recordings of rat spinal cord slices revealed that NO may S-nitrosylate voltage-activated Ca2+ channels, thereby reducing glutamate release from primary afferent terminals (Jin et al. 2011). Unlike this antinociceptive mechanism, S-nitrosylation of actin was reported to ameliorate inhibitory postsynaptic currents in the spinal dorsal horn (Lu et al. 2011). In DRG neurons, NO was found to activate ATP-sensitive potassium channels by S-nitrosylation of cysteine residues in the SURI subunit, and this effect was not blocked by inhibitors of NO-GC or cGKI (Kawano et al. 2009). Furthermore, NO directly activated TRPV1 and TRPA1 channels in isolated inside-out patch recordings (Miyamoto et al. 2009), and it seems likely that this effect is also mediated by S-nitrosylation (Yoshida et al. 2006). In a recent proteomic approach using two-dimensional S-nitrosothiol difference gel electrophoresis and S-nitrosylation-site identification in spinal cord extracts, more than 50 proteins with modified S-nitrosylation in response to peripheral nerve injury were detected. The modified proteins are involved in synaptic signaling, protein folding and transport, mitochondrial function, and redox control (Scheving et al. 2012). The functional contribution of most of these proteins to pain processing is currently unknown; however, it seems very likely that S-nitrosylation essentially contributes to cGMP-independent NO signaling in the nociceptive system.
3.4 Peroxynitrite Formation
Another mechanism of cGMP-independent NO signaling is the reaction of NO with the reactive oxygen species superoxide (O2 −) to form peroxynitrite (ONOO−) (Beckman et al. 1990). There are numerous potential sources of superoxide within cells, including mitochondria, xanthine oxidase, cyclooxygenases, cytochrome P450 monooxygenases, lipoxygenases, uncoupled endothelial NOS, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. The latter comprise a family of enzymes that rely on NADPH for their activity and are increasingly recognized as important sources of reactive oxygen species in the nociceptive system (Ibi et al. 2008; Kim et al. 2010; Kallenborn-Gerhardt et al. 2012, 2013; Lim et al. 2013). Recent studies suggest that peroxynitrite is produced during pain processing and has mainly pronociceptive properties (for review, see Salvemini et al. 2011). Accordingly, peroxynitrite decomposition catalysts attenuated inflammatory and neuropathic pain behaviors in rodents (Ndengele et al. 2008; Chen et al. 2010; Doyle et al. 2012). So far identified targets of peroxynitrite in the spinal cord include cyclooxygenases (Ndengele et al. 2008), cytokines (TNF-α and interleukin 1β, 4, and 10), and glia-derived proteins involved in glutamatergic neurotransmission (glutamate transporters and glutamine synthetase) (Chen et al. 2010; Doyle et al. 2012). Hence, peroxynitrite formation seems to be an additional factor that contributes to the multiple pain-relevant effects of NO in the spinal cord.
4 Conclusion
The processing of persistent inflammatory and neuropathic pain is associated with production of NO in the spinal cord. Over the past decade, our knowledge about the downstream signaling pathways has significantly increased. NO leads to cGMP formation in distinct cells of the nociceptive system and to activation of downstream targets including CNG channels. In addition, NO may signal in a cGMP-independent manner by S-nitrosylation of target proteins and by formation of peroxynitrite. There is strong evidence that inhibition of NO production leads to a profound reduction of inflammatory and neuropathic pain. On the other hand, NO production can also reduce pain under several conditions, because NO activates both pro- and antinociceptive mechanisms. Specific targeting of NO-dependent signaling mechanisms might offer new avenues for the treatment of pain.
Abbreviations
- cGKI:
-
cGMP-dependent protein kinase I (synonym PKG-1, protein kinase G-1)
- cGMP:
-
3′, 5′-cyclic guanosine monophosphate
- CNG:
-
Cyclic-nucleotide gated
- DRG:
-
Dorsal root ganglion
- GC-A:
-
Particulate guanylyl cyclase A (synonym NPR-A, natriuretic peptide receptor A)
- GC-B:
-
Particulate guanylyl cyclase B (synonym NPR-B, natriuretic peptide receptor B)
- HCN:
-
Hyperpolarization activated and cyclic-nucleotide gated
- NO:
-
Nitric oxide
- NO-GC:
-
NO-sensitive guanylyl cyclase (synonym sGC, soluble guanylyl cyclase)
- NOS:
-
NO synthase
- PDE:
-
Phosphodiesterase
References
Aimi Y, Fujimura M, Vincent SR, Kimura H (1991) Localization of NADPH-diaphorase-containing neurons in sensory ganglia of the rat. J Comp Neurol 306:382–392
Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A 87:1620–1624
Bernardi PS, Valtschanoff JG, Weinberg RJ, Schmidt HH, Rustioni A (1995) Synaptic interactions between primary afferent terminals and GABA and nitric oxide-synthesizing neurons in superficial laminae of the rat spinal cord. J Neurosci 15:1363–1371
Berrazueta JR, Losada A, Poveda J, Ochoteco A, Riestra A, Salas E, Amado JA (1996) Successful treatment of shoulder pain syndrome due to supraspinatus tendinitis with transdermal nitroglycerin. A double blind study. Pain 66:63–67
Bian K, Ke Y, Kamisaki Y, Murad F (2006) Proteomic modification by nitric oxide. J Pharmacol Sci 101:271–279
Boettger MK, Uceyler N, Zelenka M, Schmitt A, Reif A, Chen Y, Sommer C (2007) Differences in inflammatory pain in nNOS-, iNOS- and eNOS-deficient mice. Eur J Pain 11:810–818
Burgoyne JR, Madhani M, Cuello F, Charles RL, Brennan JP, Schroder E, Browning DD, Eaton P (2007) Cysteine redox sensor in PKGIa enables oxidant-induced activation. Science 317:1393–1397
Cadiou H, Studer M, Jones NG, Smith ES, Ballard A, McMahon SB, McNaughton PA (2007) Modulation of acid-sensing ion channel activity by nitric oxide. J Neurosci 27:13251–13260
Chen Z, Muscoli C, Doyle T, Bryant L, Cuzzocrea S, Mollace V, Mastroianni R, Masini E, Salvemini D (2010) NMDA-receptor activation and nitroxidative regulation of the glutamatergic pathway during nociceptive processing. Pain 149:100–106
Chu YC, Guan Y, Skinner J, Raja SN, Johns RA, Tao YX (2005) Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund’s adjuvant-induced persistent pain. Pain 119:113–123
Craven KB, Zagotta WN (2006) CNG and HCN channels: two peas, one pod. Annu Rev Physiol 68:375–401
Dableh LJ, Henry JL (2011) The selective neuronal nitric oxide synthase inhibitor 7-nitroindazole has acute analgesic but not cumulative effects in a rat model of peripheral neuropathy. J Pain Res 4:85–90
De Alba J, Clayton NM, Collins SD, Colthup P, Chessell I, Knowles RG (2006) GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. Pain 120:170–181
Ding JD, Weinberg RJ (2006) Localization of soluble guanylyl cyclase in the superficial dorsal horn. J Comp Neurol 495:668–678
Doyle T, Chen Z, Muscoli C, Bryant L, Esposito E, Cuzzocrea S, Dagostino C, Ryerse J, Rausaria S, Kamadulski A, Neumann WL, Salvemini D (2012) Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain. J Neurosci 32:6149–6160
Dun NJ, Dun SL, Wu SY, Forstermann U, Schmidt HH, Tseng LF (1993) Nitric oxide synthase immunoreactivity in the rat, mouse, cat and squirrel monkey spinal cord. Neuroscience 54:845–857
Eliasson MJ, Blackshaw S, Schell MJ, Snyder SH (1997) Neuronal nitric oxide synthase alternatively spliced forms: prominent functional localizations in the brain. Proc Natl Acad Sci U S A 94:3396–3401
Feil R, Kleppisch T (2008) NO/cGMP-dependent modulation of synaptic transmission. Handb Exp Pharmacol (184):529–560
Ferreira J, Santos AR, Calixto JB (1999) The role of systemic, spinal and supraspinal L-arginine-nitric oxide-cGMP pathway in thermal hyperalgesia caused by intrathecal injection of glutamate in mice. Neuropharmacology 38:835–842
Francis SH, Busch JL, Corbin JD, Sibley D (2010) cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev 62:525–563
Friebe A, Mergia E, Dangel O, Lange A, Koesling D (2007) Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase. Proc Natl Acad Sci U S A 104:7699–7704
Garbers DL, Chrisman TD, Wiegn P, Katafuchi T, Albanesi JP, Bielinski V, Barylko B, Redfield MM, Burnett JC Jr (2006) Membrane guanylyl cyclase receptors: an update. Trends Endocrinol Metab 17:251–258
Garry MG, Abraham E, Hargreaves KM, Aanonsen LM (1994) Intrathecal injection of cell-permeable analogs of cyclic 3′,5′-guanosine monophosphate produces hyperalgesia in mice. Eur J Pharmacol 260:129–131
Gassner M, Leitner J, Gruber-Schoffnegger D, Forsthuber L, Sandkuhler J (2013) Properties of spinal lamina III GABAergic neurons in naive and in neuropathic mice. Eur J Pain 17:1168–1179
Guan Y, Yaster M, Raja SN, Tao YX (2007) Genetic knockout and pharmacologic inhibition of neuronal nitric oxide synthase attenuate nerve injury-induced mechanical hypersensitivity in mice. Mol Pain 3:29
Guhring H, Gorig M, Ates M, Coste O, Zeilhofer HU, Pahl A, Rehse K, Brune K (2000) Suppressed injury-induced rise in spinal prostaglandin E2 production and reduced early thermal hyperalgesia in iNOS-deficient mice. J Neurosci 20:6714–6720
Haley JE, Dickenson AH, Schachter M (1992) Electrophysiological evidence for a role of nitric oxide in prolonged chemical nociception in the rat. Neuropharmacology 31:251–258
Heine S, Michalakis S, Kallenborn-Gerhardt W, Lu R, Lim HY, Weiland J, Del Turco D, Deller T, Tegeder I, Biel M, Geisslinger G, Schmidtko A (2011) CNGA3: a target of spinal NO/cGMP signaling and modulator of inflammatory pain hypersensitivity. J Neurosci 31:11184–11192
Henrich M, Hoffmann K, Konig P, Gruss M, Fischbach T, Godecke A, Hempelmann G, Kummer W (2002) Sensory neurons respond to hypoxia with NO production associated with mitochondria. Mol Cell Neurosci 20:307–322
Herdegen T, Rudiger S, Mayer B, Bravo R, Zimmermann M (1994) Expression of nitric oxide synthase and colocalisation with Jun, Fos and Krox transcription factors in spinal cord neurons following noxious stimulation of the rat hindpaw. Brain Res Mol Brain Res 22:245–258
Hervera A, Negrete R, Leanez S, Martin-Campos JM, Pol O (2010) The spinal cord expression of neuronal and inducible nitric oxide synthases and their contribution in the maintenance of neuropathic pain in mice. PLoS One 5:e14321
Hervera A, Leanez S, Negrete R, Motterlini R, Pol O (2012) Carbon monoxide reduces neuropathic pain and spinal microglial activation by inhibiting nitric oxide synthesis in mice. PLoS One 7:e43693
Hess DT, Matsumoto A, Kim SO, Marshall HE, Stamler JS (2005) Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol 6:150–166
Hughes AS, Averill S, King VR, Molander C, Shortland PJ (2008) Neurochemical characterization of neuronal populations expressing protein kinase C gamma isoform in the spinal cord and gracile nucleus of the rat. Neuroscience 153:507–517
Ibi M, Matsuno K, Shiba D, Katsuyama M, Iwata K, Kakehi T, Nakagawa T, Sango K, Shirai Y, Yokoyama T, Kaneko S, Saito N, Yabe-Nishimura C (2008) Reactive oxygen species derived from NOX1/NADPH oxidase enhance inflammatory pain. J Neurosci 28:9486–9494
Ikeda H, Stark J, Fischer H, Wagner M, Drdla R, Jager T, Sandkuhler J (2006) Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 312:1659–1662
Iwamoto ET, Marion L (1994) Pharmacologic evidence that spinal muscarinic analgesia is mediated by an L-arginine/nitric oxide/cyclic GMP cascade in rats. J Pharmacol Exp Ther 271:601–608
Jin XG, Chen SR, Cao XH, Li L, Pan HL (2011) Nitric oxide inhibits nociceptive transmission by differentially regulating glutamate and glycine release to spinal dorsal horn neurons. J Biol Chem 286:33190–33202
Kallenborn-Gerhardt W, Schroder K, Del Turco D, Lu R, Kynast K, Kosowski J, Niederberger E, Shah AM, Brandes RP, Geisslinger G, Schmidtko A (2012) NADPH oxidase-4 maintains neuropathic pain after peripheral nerve injury. J Neurosci 32:10136–10145
Kallenborn-Gerhardt W, Schroder K, Geisslinger G, Schmidtko A (2013) NOXious signaling in pain processing. Pharmacol Ther 137:309–317
Kawamata T, Omote K (1999) Activation of spinal N-methyl-D-aspartate receptors stimulates a nitric oxide/cyclic guanosine 3,5-monophosphate/glutamate release cascade in nociceptive signaling. Anesthesiology 91:1415–1424
Kawano T, Zoga V, Kimura M, Liang MY, Wu HE, Gemes G, McCallum JB, Kwok WM, Hogan QH, Sarantopoulos CD (2009) Nitric oxide activates ATP-sensitive potassium channels in mammalian sensory neurons: action by direct S-nitrosylation. Mol Pain 5:12
Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH, Gao YJ, Roy K, Corfas G, Lo EH, Ji RR (2008) Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 14:331–336
Keilhoff G, Fansa H, Wolf G (2002) Neuronal nitric oxide synthase is the dominant nitric oxide supplier for the survival of dorsal root ganglia after peripheral nerve axotomy. J Chem Neuroanat 24:181–187
Keilhoff G, Schroder H, Peters B, Becker A (2013) Time-course of neuropathic pain in mice deficient in neuronal or inducible nitric oxide synthase. Neurosci Res 77:215–221
Kim D, You B, Jo EK, Han SK, Simon MI, Lee SJ (2010) NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain. Proc Natl Acad Sci U S A 107:14851–14856
Kina VA, Villarreal CF, Prado WA (2005) The effects of intraspinal L-NOARG or SIN-1 on the control by descending pathways of incisional pain in rats. Life Sci 76:1939–1951
Kishimoto I, Tokudome T, Horio T, Soeki T, Chusho H, Nakao K, Kangawa K (2008) C-type natriuretic peptide is a Schwann cell-derived factor for development and function of sensory neurons. J Neuroendocrinol 20:1213–1223
Kitto KF, Haley JE, Wilcox GL (1992) Involvement of nitric oxide in spinally mediated hyperalgesia in the mouse. Neurosci Lett 148:1–5
Kuboyama K, Tsuda M, Tsutsui M, Toyohara Y, Tozaki-Saitoh H, Shimokawa H, Yanagihara N, Inoue K (2011) Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases. Mol Pain 7:50
Laing I, Todd AJ, Heizmann CW, Schmidt HH (1994) Subpopulations of GABAergic neurons in laminae I-III of rat spinal dorsal horn defined by coexistence with classical transmitters, peptides, nitric oxide synthase or parvalbumin. Neuroscience 61:123–132
Lauretti GR, Lima IC, Reis MP, Prado WA, Pereira NL (1999a) Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology 90:1528–1533
Lauretti GR, de Oliveira R, Reis MP, Mattos AL, Pereira NL (1999b) Transdermal nitroglycerine enhances spinal sufentanil postoperative analgesia following orthopedic surgery. Anesthesiology 90:734–739
Lim H, Kim D, Lee SJ (2013) Toll-like receptor 2 mediates peripheral nerve injury-induced NADPH oxidase 2 expression in spinal cord microglia. J Biol Chem 288:7572–7579
Lin Q, Palecek J, Paleckova V, Peng YB, Wu J, Cui M, Willis WD (1999) Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons. J Neurophysiol 81:1075–1085
Loo L, Shepherd AJ, Mickle AD, Lorca RA, Shutov LP, Usachev YM, Mohapatra DP (2012) The C-type natriuretic peptide induces thermal hyperalgesia through a noncanonical Gbetagamma-dependent modulation of TRPV1 channel. J Neurosci 32:11942–11955
Lorenz JE, Kallenborn-Gerhardt W, Lu R, Syhr KM, Eaton P, Geisslinger G, Schmidtko A (2014) Oxidant-induced activation of cGMP-dependent protein kinase Iα mediates neuropathic pain after peripheral nerve injury. Antioxid Redox Signal 21(10):1504–1515
Lu J, Katano T, Uta D, Furue H, Ito S (2011) Rapid S-nitrosylation of actin by NO-generating donors and in inflammatory pain model mice. Mol Pain 7:101
Lu R, Lukowski R, Sausbier M, Zhang DD, Sisignano M, Schuh CD, Kuner R, Ruth P, Geisslinger G, Schmidtko A (2014) BKCa channels expressed in sensory neurons modulate inflammatory pain in mice. Pain 155(3):556–565
Luo ZD, Cizkova D (2000) The role of nitric oxide in nociception. Curr Rev Pain 4:459–466
Luo ZD, Chaplan SR, Scott BP, Cizkova D, Calcutt NA, Yaksh TL (1999) Neuronal nitric oxide synthase mRNA upregulation in rat sensory neurons after spinal nerve ligation: lack of a role in allodynia development. J Neurosci 19:9201–9208
Luo C, Gangadharan V, Bali KK, Xie RG, Agarwal N, Kurejova M, Tappe-Theodor A, Tegeder I, Feil S, Lewin G, Polgar E, Todd AJ, Schlossmann J, Hofmann F, Liu DL, Hu SJ, Feil R, Kuner T, Kuner R (2012) Presynaptically localized cyclic GMP-dependent protein kinase 1 is a key determinant of spinal synaptic potentiation and pain hypersensitivity. PLoS Biol 10:e1001283
Machelska H, Przewlocki R, Radomski MW, Przewlocka B (1998) Differential effects of intrathecally and intracerebroventricularly administered nitric oxide donors on noxious mechanical and thermal stimulation. Pol J Pharmacol 50:407–415
Maihofner C, Euchenhofer C, Tegeder I, Beck KF, Pfeilschifter J, Geisslinger G (2000) Regulation and immunohistochemical localization of nitric oxide synthases and soluble guanylyl cyclase in mouse spinal cord following nociceptive stimulation. Neurosci Lett 290:71–75
Mantyh PW, Hunt SP (2004) Setting the tone: superficial dorsal horn projection neurons regulate pain sensitivity. Trends Neurosci 27:582–584
Martucci C, Trovato AE, Costa B, Borsani E, Franchi S, Magnaghi V, Panerai AE, Rodella LF, Valsecchi AE, Sacerdote P, Colleoni M (2008) The purinergic antagonist PPADS reduces pain related behaviours and interleukin-1beta, interleukin-6, iNOS and nNOS overproduction in central and peripheral nervous system after peripheral neuropathy in mice. Pain 137:81–95
Meller ST, Gebhart GF (1993) Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 52:127–136
Meller ST, Dykstra C, Gebhart GF (1992) Production of endogenous nitric oxide and activation of soluble guanylate cyclase are required for N-methyl-D-aspartate-produced facilitation of the nociceptive tail-flick reflex. Eur J Pharmacol 214:93–96
Miyamoto T, Dubin AE, Petrus MJ, Patapoutian A (2009) TRPV1 and TRPA1 mediate peripheral nitric oxide-induced nociception in mice. PLoS One 4:e7596
Morris R, Southam E, Braid DJ, Garthwaite J (1992) Nitric oxide may act as a messenger between dorsal root ganglion neurones and their satellite cells. Neurosci Lett 137:29–32
Ndengele MM, Cuzzocrea S, Esposito E, Mazzon E, Di Paola R, Matuschak GM, Salvemini D (2008) Cyclooxygenases 1 and 2 contribute to peroxynitrite-mediated inflammatory pain hypersensitivity. FASEB J 22:3154–3164
Paoloni JA, Appleyard RC, Nelson J, Murrell GA (2003) Topical nitric oxide application in the treatment of chronic extensor tendinosis at the elbow: a randomized, double-blinded, placebo-controlled clinical trial. Am J Sports Med 31:915–920
Pehl U, Schmid HA (1997) Electrophysiological responses of neurons in the rat spinal cord to nitric oxide. Neuroscience 77:563–573
Polgar E, Sardella TC, Tiong SY, Locke S, Watanabe M, Todd AJ (2013) Functional differences between neurochemically defined populations of inhibitory interneurons in the rat spinal dorsal horn. Pain 154:2606–2615
Puskar Z, Polgar E, Todd AJ (2001) A population of large lamina I projection neurons with selective inhibitory input in rat spinal cord. Neuroscience 102:167–176
Qian Y, Chao DS, Santillano DR, Cornwell TL, Nairn AC, Greengard P, Lincoln TM, Bredt DS (1996) cGMP-dependent protein kinase in dorsal root ganglion: relationship with nitric oxide synthase and nociceptive neurons. J Neurosci 16:3130–3138
Ruscheweyh R, Goralczyk A, Wunderbaldinger G, Schober A, Sandkuhler J (2006) Possible sources and sites of action of the nitric oxide involved in synaptic plasticity at spinal lamina I projection neurons. Neuroscience 141:977–988
Saito S, Kidd GJ, Trapp BD, Dawson TM, Bredt DS, Wilson DA, Traystman RJ, Snyder SH, Hanley DF (1994) Rat spinal cord neurons contain nitric oxide synthase. Neuroscience 59:447–456
Salvemini D, Little JW, Doyle T, Neumann WL (2011) Roles of reactive oxygen and nitrogen species in pain. Free Radic Biol Med 51:951–966
Sardella TC, Polgar E, Watanabe M, Todd AJ (2011) A quantitative study of neuronal nitric oxide synthase expression in laminae I-III of the rat spinal dorsal horn. Neuroscience 192:708–720
Scheving R, Wittig I, Heide H, Albuquerque B, Steger M, Brandt U, Tegeder I (2012) Protein S-nitrosylation and denitrosylation in the mouse spinal cord upon injury of the sciatic nerve. J Proteomics 75:3987–4004
Schmidt H, Stonkute A, Juttner R, Schaffer S, Buttgereit J, Feil R, Hofmann F, Rathjen FG (2007) The receptor guanylyl cyclase Npr2 is essential for sensory axon bifurcation within the spinal cord. J Cell Biol 179:331–340
Schmidtko A, Ruth P, Geisslinger G, Tegeder I (2003) Inhibition of cyclic guanosine 5′-monophosphate-dependent protein kinase I (PKG-I) in lumbar spinal cord reduces formalin-induced hyperalgesia and PKG upregulation. Nitric Oxide 8:89–94
Schmidtko A, Gao W, Konig P, Heine S, Motterlini R, Ruth P, Schlossmann J, Koesling D, Niederberger E, Tegeder I, Friebe A, Geisslinger G (2008a) cGMP produced by NO-sensitive guanylyl cyclase essentially contributes to inflammatory and neuropathic pain by using targets different from cGMP-dependent protein kinase I. J Neurosci 28:8568–8576
Schmidtko A, Gao W, Sausbier M, Rauhmeier I, Sausbier U, Niederberger E, Scholich K, Huber A, Neuhuber W, Allescher HD, Hofmann F, Tegeder I, Ruth P, Geisslinger G (2008b) Cysteine-rich protein 2, a novel downstream effector of cGMP/cGMP-dependent protein kinase I-mediated persistent inflammatory pain. J Neurosci 28:1320–1330
Schmidtko A, Tegeder I, Geisslinger G (2009) No NO, no pain? The role of nitric oxide and cGMP in spinal pain processing. Trends Neurosci 32:339–346
Scholz J, Woolf CJ (2007) The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 10:1361–1368
Shi TJ, Holmberg K, Xu ZQ, Steinbusch H, de Vente J, Hokfelt T (1998) Effect of peripheral nerve injury on cGMP and nitric oxide synthase levels in rat dorsal root ganglia: time course and coexistence. Pain 78:171–180
Song XJ, Wang ZB, Gan Q, Walters ET (2006) cAMP and cGMP contribute to sensory neuron hyperexcitability and hyperalgesia in rats with dorsal root ganglia compression. J Neurophysiol 95:479–492
Sousa AM, Prado WA (2001) The dual effect of a nitric oxide donor in nociception. Brain Res 897:9–19
Spike RC, Todd AJ, Johnston HM (1993) Coexistence of NADPH diaphorase with GABA, glycine, and acetylcholine in rat spinal cord. J Comp Neurol 335:320–333
Sung YJ, Walters ET, Ambron RT (2004) A neuronal isoform of protein kinase G couples mitogen-activated protein kinase nuclear import to axotomy-induced long-term hyperexcitability in Aplysia sensory neurons. J Neurosci 24:7583–7595
Sung YJ, Chiu DT, Ambron RT (2006) Activation and retrograde transport of protein kinase G in rat nociceptive neurons after nerve injury and inflammation. Neuroscience 141:697–709
Tang Q, Svensson CI, Fitzsimmons B, Webb M, Yaksh TL, Hua XY (2007) Inhibition of spinal constitutive NOS-2 by 1400W attenuates tissue injury and inflammation-induced hyperalgesia and spinal p38 activation. Eur J Neurosci 25:2964–2972
Tao YX, Johns RA (2002) Activation and up-regulation of spinal cord nitric oxide receptor, soluble guanylate cyclase, after formalin injection into the rat hind paw. Neuroscience 112:439–446
Tao YX, Hassan A, Haddad E, Johns RA (2000) Expression and action of cyclic GMP-dependent protein kinase Ialpha in inflammatory hyperalgesia in rat spinal cord. Neuroscience 95:525–533
Tao F, Tao YX, Mao P, Zhao C, Li D, Liaw WJ, Raja SN, Johns RA (2003) Intact carrageenan-induced thermal hyperalgesia in mice lacking inducible nitric oxide synthase. Neuroscience 120:847–854
Tao F, Tao YX, Zhao C, Dore S, Liaw WJ, Raja SN, Johns RA (2004) Differential roles of neuronal and endothelial nitric oxide synthases during carrageenan-induced inflammatory hyperalgesia. Neuroscience 128:421–430
Tegeder I, Schmidtko A, Niederberger E, Ruth P, Geisslinger G (2002) Dual effects of spinally delivered 8-bromo-cyclic guanosine mono-phosphate (8-bromo-cGMP) in formalin-induced nociception in rats. Neurosci Lett 332:146–150
Tegeder I, Del Turco D, Schmidtko A, Sausbier M, Feil R, Hofmann F, Deller T, Ruth P, Geisslinger G (2004) Reduced inflammatory hyperalgesia with preservation of acute thermal nociception in mice lacking cGMP-dependent protein kinase I. Proc Natl Acad Sci U S A 101:3253–3257
Tegeder I, Scheving R, Wittig I, Geisslinger G (2011) SNO-ing at the nociceptive synapse? Pharmacol Rev 63:366–389
Tiong SY, Polgar E, van Kralingen JC, Watanabe M, Todd AJ (2011) Galanin-immunoreactivity identifies a distinct population of inhibitory interneurons in laminae I-III of the rat spinal cord. Mol Pain 7:36
Valtschanoff JG, Weinberg RJ, Rustioni A, Schmidt HH (1992) Nitric oxide synthase and GABA colocalize in lamina II of rat spinal cord. Neurosci Lett 148:6–10
Wu J, Lin Q, Lu Y, Willis WD, Westlund KN (1998) Changes in nitric oxide synthase isoforms in the spinal cord of rat following induction of chronic arthritis. Exp Brain Res 118:457–465
Yonehara N, Takemura M, Yoshimura M, Iwase K, Seo HG, Taniguchi N, Shigenaga Y (1997) Nitric oxide in the rat spinal cord in Freund’s adjuvant-induced hyperalgesia. Jpn J Pharmacol 75:327–335
Yoshida T, Inoue R, Morii T, Takahashi N, Yamamoto S, Hara Y, Tominaga M, Shimizu S, Sato Y, Mori Y (2006) Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat Chem Biol 2:596–607
Zhang X, Verge V, Wiesenfeld-Hallin Z, Ju G, Bredt D, Synder SH, Hokfelt T (1993) Nitric oxide synthase-like immunoreactivity in lumbar dorsal root ganglia and spinal cord of rat and monkey and effect of peripheral axotomy. J Comp Neurol 335:563–575
Zhang X, Chen Y, Wang C, Huang LY (2007) Neuronal somatic ATP release triggers neuron-satellite glial cell communication in dorsal root ganglia. Proc Natl Acad Sci U S A 104:9864–9869
Zhang FX, Liu XJ, Gong LQ, Yao JR, Li KC, Li ZY, Lin LB, Lu YJ, Xiao HS, Bao L, Zhang XH, Zhang X (2010) Inhibition of inflammatory pain by activating B-type natriuretic peptide signal pathway in nociceptive sensory neurons. J Neurosci 30:10927–10938
Zhuang ZY, Gerner P, Woolf CJ, Ji RR (2005) ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 114:149–159
Zhuo M, Meller ST, Gebhart GF (1993) Endogenous nitric oxide is required for tonic cholinergic inhibition of spinal mechanical transmission. Pain 54:71–78
Acknowledgments
Related work done in the author’s laboratory was supported by the Deutsche Forschungsgemeinschaft, Witten/Herdecke University, and Doktor Robert Pfleger-Stiftung.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Schmidtko, A. (2015). Nitric Oxide-Mediated Pain Processing in the Spinal Cord. In: Schaible, HG. (eds) Pain Control. Handbook of Experimental Pharmacology, vol 227. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-46450-2_6
Download citation
DOI: https://doi.org/10.1007/978-3-662-46450-2_6
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-46449-6
Online ISBN: 978-3-662-46450-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)