Mer om NO sin funksjon som både smertedempende og smerteøkende. Nevner alle faktorer som spiller inn i både nervesystem, ryggmarg og perifert. Viktig studie som også indirekte kan brukes i å forstå sammenhengen mellom hvordan CO2 og økning av eNOS (i blodkar) kan dempe nNOS (i nervesystemet).

http://www.jbc.org/content/286/38/33190.full

«Our findings suggest that spinal endogenous NO enhances inhibitory glycinergic input to dorsal horn neurons through sGC-cGMP-protein kinase G. Furthermore, NO reduces glutamate release from primary afferent terminals through S-nitrosylation of voltage-activated Ca2+ channels. Both of these actions probably contribute to inhibition of nociceptive transmission by NO at the spinal level.»

«Nitric oxide (NO) is freely diffusible across the cell membranes and is synthesized by the nitric-oxide synthase (NOS)2 from L-arginine and different cofactors.»

«The three NOS isoforms, including neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), have distinct structures and functions (1, 2). »

Refererer til Superoxid, den viktigste antioksidanten som CO2 beskytter. Og til peroxynitritt, den farligste oksidanten som CO2 også beskytter mot.

«The diverse effects of NO is commonly mediated through increased cGMP production upon activation of NO-sensitive soluble guanylyl cyclase (sGC), S-nitrosylation, tyrosine nitration, and the interaction with superoxide to form peroxynitrite (3,–,5). »

Hvordan NO gir smerte, og at NO-hemmere demper smerte.:
«Some studies suggest that spinal NO is involved in the potentiation of nociception. For example, mechanical hypersensitivity induced by nerve injury or tissue inflammation is reduced by intrathecal administration of nNOS inhibitors and in nNOS-knock-out mice (6, 9, 10). »

Hvordan NO demper smerte:
«In contrast, other studies have shown that spinal NO plays a role in the inhibition of nociceptive processing. In this regard, intrathecal administration of L-arginine increases the mechanical nociceptive withdrawal threshold in rats (12). »

Mengden har mye å si for effekten, med lite er det smertedempende, men mye er det smerteøkende.
«For instance, it has been shown that intrathecal injection of low doses of L-arginine or NO donors reduce nociception, but L-arginine or NO donors at the high doses potentiates nociceptive responses to formalin injection or nerve injury (16, 17).»

Nevner at hvis én type NO er nedregulert blir en annen type oppregulert. Muligheten er da for at om eNOS (i blodårer) er lav pga dårlig blodsirkulasjon og lite CO2, kan nNOS (i nervesystemet) økes og dermed gi smerter. Ved å øke eNOS kan man da få mindre nNOS og dermed en indirekte smertedemping.
«In addition, it should be noted that in eNOS-, nNOS-, or iNOS-knock-out mice, an increase in the expression of other NOS isoforms in the spinal cord has been reported (18, 19). This compensatory up-regulation of other NOS subtypes in specific NOS isoform-knock-out mice further confounds the interpretation of the results.»

Om at NO både øker nocicepsjon og demper den:

«The discrepancy may result from the use of different pain models, the amount of NO produced locally, and the specific CNS sites involved. For example, NO-cGMP inhibits dorsal horn neuronal activity at the spinal level but excites spinal dorsal horn neurons at the supraspinal level (15, 39). Also, while low concentrations of NO inhibit NMDA receptor activity (40, 41), high concentrations of NO stimulate TRPV1 and TRPA1 receptors (42). »

«GABA and glycine are the two predominant inhibitory neurotransmitters in the spinal cord. Blocking GABA_A or glycine receptors in the spinal cord induces pain hypersensitivity in rats (43, 44).»

«Of note, L-arginine and SNAP had similar effects on glycinergic sIPSCs and mIPSCs, suggesting that NO can potentiate glycine release from presynaptic terminals of interneurons in the spinal dorsal horn. Thus, our findings indicate that NO potentiates glycinergic input to spinal dorsal horn neurons to attenuate nociceptive transmission.»

«Glutamate is an excitatory neurotransmitter critically involved in nociceptive transmission in the spinal dorsal horn. In this study, we found that L-arginine and SNAP significantly inhibited the frequency of glutamatergic sEPSCs of lamina II neurons. L-Arginine and SNAP also consistently inhibited glutamatergic EPSCs evoked from primary afferents in most lamina II neurons.»

«Thus, it is unlikely that the inhibitory effect of NO on synaptic glutamate release to dorsal horn neurons is secondary to increased glycine release and stimulation of presynaptic glycine receptors (35). Our findings strongly suggest that NO attenuates synaptic glutamate release by inhibition of HVACCs at primary afferent terminals.»

«Another salient finding of our study is that NO potentiates glycinergic input and inhibits glutamatergic synaptic transmission in the spinal dorsal horn through distinct signaling pathways.»

«Therefore, our findings suggest that spinal NO primarily inhibits glutamate release through S-nitrosylation of HVACCs at primary afferent terminals.»

«In addition to its inhibitory effect on HVACCs shown in our study, NO can inhibit NMDA receptor currents in recombinant systems (60, 61) and in spinal lamina II neurons (41). Because both HVACCs and NMDA receptors are critically involved in nociceptive transmission, it seems difficult to explain the proposed pronociceptive role of NO at the spinal level. Of note, systemic use of NO or NO donors has been shown to reduce pain intensity caused by sickle cell crisis or diabetic neuropathy in patients (62, 63). We found in the present study that intrathecal administration of L-arginine or SNAP in rats significantly increased the nociceptive mechanical thresholds.»

«Hence, NMDA receptor activation could lead to increased NO production and release, and NO can diffuse to the presynaptic site to reduce glutamate release from primary afferent terminals. By reducing glutamatergic transmission, NO could serve as a feedback regulator to attenuate nociceptive transmission at the spinal level during painful conditions.»

«In summary, our study provides important new evidence that spinal NO potentiates inhibitory glycinergic input but reduces glutamatergic synaptic transmission between primary afferents and dorsal horn neurons through distinct signaling mechanisms. The opposing effects of NO on glutamatergic and glycinergic synaptic transmission could contribute to the antinociceptive effect of NO at the spinal level. This new information is important for our understanding of the synaptic actions underlying the antinociceptive effect of NO at the spinal level.»