Possible sources and sites of action of the nitric oxide involved in synaptic plasticity at spinal lamina i projection neurons

cGMP Produced by NO-Sensitive Guanylyl Cyclase Essentially Contributes to Inflammatory and Neuropathic Pain by Using Targets Different from cGMP-Dependent Protein Kinase I

“…Using an anti-GC␤ 1 antibody (Friebe et al, 2007) whose specificity was confirmed by immunohistochemical and Western blot analyses in tissue of GC-KO mice, we here demonstrate that NO-GC is expressed in NK1-R-positive projection neurons and in GAD67-positive inhibitory interneurons, whereas it is absent in central terminals of primary afferent neurons and in glial cells of the mouse spinal cord. This staining pattern is similar to the distribution of NO-GC in the spinal cord of rats that was reported recently by Ruscheweyh et al (2006) and Ding (2006). In DRGs, we found NO-GC to be expressed in satellite cells, pericytes, and smooth muscle cells of blood vessels, but unexpectedly not in neurons.…”

“…The distribution of NO-GC in the spinal cord and DRGs has been investigated in previous studies using antibodies from different sources with, however, contradictory results (Maihöfner et al, 2000;Tao and Johns, 2002;Ding and Weinberg, 2006;Ruscheweyh et al, 2006). Using an anti-GC␤ 1 antibody (Friebe et al, 2007) whose specificity was confirmed by immunohistochemical and Western blot analyses in tissue of GC-KO mice, we here demonstrate that NO-GC is expressed in NK1-R-positive projection neurons and in GAD67-positive inhibitory interneurons, whereas it is absent in central terminals of primary afferent neurons and in glial cells of the mouse spinal cord.…”

SNO-ing at the Nociceptive Synapse?

“…It is also expressed in lamina III interneurons in the spinal cord and few deep dorsal horn neurons (Maihöfner et al, 2000a). At all these sites, the expression increases upon peripheral inflammation or nerve injury, which is accompanied by an up-regulation of PKG in DRG neurons (Zhang et al, 1993;Vizzard et al, 1995;Maihöfner et al, 2000a;Tegeder et al, 2004a;Ruscheweyh et al, 2006;Schmidtko et al, 2008a). The localization and up-regulation raises the possibility that NO produced in DRG neurons directly activates PKG, through a mechanism independent of cGMP.…”

CNGA3: A Target of Spinal Nitric Oxide/cGMP Signaling and Modulator of Inflammatory Pain Hypersensitivity

“…Pronociceptive effects of cGMP are also mediated by NO-dependent activation of NO-GC, as indicated by the considerably reduced nociceptive behavior in mice lacking NO-GC (Schmidtko et al, 2008a). However, NO-GC is expressed in different areas of the spinal cord, i.e., in NK1 receptor-positive projection neurons in lamina I and in inhibitory interneurons of the dorsal horn, as well as in DRG satellite glial cells (Ding and Weinberg, 2006;Ruscheweyh et al, 2006;Schmidtko et al, 2008a). It is currently not known whether or not NO-GC-mediated cGMP production in all these cells results in pronociceptive effects.…”

“…Recent evidence indicates that various cGMP signaling pathways in the superficial dorsal horn of the spinal cord essentially contribute to the mechanisms underlying pain sensitization (Schmidtko et al, 2009). One "pain-relevant" cGMP-dependent signaling pathway is initiated by release of nitric oxide (NO) and subsequent cGMP production by NO-sensitive guanylyl cyclase (NO-GC; also called soluble guanylyl cyclase) in lamina I projection neurons and in inhibitory interneurons of the dorsal horn (Ding and Weinberg, 2006;Ruscheweyh et al, 2006;Schmidtko et al, 2008a). Studies with intrathecally (i.t.)…”