Nitric Oxide is Negatively Correlated to Pain during Acute Inflammation

Abstract

BackgroundThe role that nitric oxide (NO) plays in modulating pain in the periphery is unclear. We show here, the results of two independent clinical studies (microdialysis and gene expression studies) and a pilot dose finding study (glyceryl trinitrate study), to study the role of NO in the early phase of acute inflammatory pain following oral surgery. The effect of ketorolac on NO production and nitric oxide synthase (NOS) gene expression was also studied.ResultsMicrodialysis samples showed significantly higher levels of NO at the first 100 min compared to the last 80 minutes in the placebo treated group. In the ketorolac group, on the other hand, NO levels gradually decreased over the first 60 min but were similar to placebo over the later 100-180 min, with no significant change in NO level over time. The levels of NO were negatively correlated to pain intensity scores. Local infusion of the NO donor glyceryl trinitrate at the site of surgery, showed a small analgesic effect that did not reach statistical significance in the sample size used. While the gene expression of iNOS and eNOS were not up-regulated, 3 hours after surgery, nNOS was downregulated in both treatment groups and eNOS gene expression was significantly lower in the ketorolac group compared to the placebo group. Further, there was a positive correlation between the change in gene expression of nNOS and eNOS in the placebo goup but not in the ketorolac group.ConclusionWe suggest that at this early stage of inflammatory pain in man, NO is analgesic in the periphery. Further, ketorolac down-regulates eNOS gene expression.

Nitric Oxide Synthase Modulates the Antihyperalgesic Effect of the NMDA Receptor Antagonist MK-801 on Carrageenan-Induced Inflammatory Pain in Rats

“…This discrepancy may be explained by the fact that, depending on NO concentration and the presence of NOS isoforms, NO can exert dual effects on redox balance and functions of neuron subpopulations (Kawabata et al 1994;Zhang et al 2006). The majority of data suggest a pronociceptive role of NO at the spinal level (Boettger et al 2007;Schmidtko et al 2009), while some studies indicate that NO is analgesic in the periphery in the early stage of inflammatory pain (Hamza et al 2010). In general, inappropriate or excessive NO produced by iNOS and/or nNOS is associated with inflammatory and neuropathic pain (Payne et al 2010).…”

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…Inhibition of NOS or GC without sildenafil augmented the diabetes-induced hyperalgesia while in healthy animals sildenafil, NOS, or GC inhibitor failed to alter mechanonociception. In humans having undergone extraction of impacted third molar, NO levels at the surgical site gradually increased over the first 80 min compared with the rest of the 180-min observation period, and an inverse relationship between NO levels and pain intensity scores was revealed (264). All these data argue for a local antihyperalgesic effect of the NO-GCcGMP pathway that is not tonically active but stimulated by diverse hyperalgesia-inducing agents/conditions including PGE 2 , bradykinin, cytokines, carrageenan, diabetes, and oral surgery.…”

Nitric oxide as a messenger between neurons and satellite glial cells in dorsal root ganglia

“…Similar conclusions were reached in work on animals (Aley et al, ; Kim, Kim, Han, Choe, & Ahn, ). However, there are studies indicating an analgesic action of NO in the periphery in both humans (Hamza et al, ) and animals (Ventura‐Martínez, Déciga‐Campos, Díaz‐Reval, González‐Trujano, & López‐Muñoz, ).…”