Nitric oxide plays an important role in various biological processes including antinociception. The control of its local concentration is crucial for obtaining the desired effect and can be achieved with exogenous
nitric oxide-carriers such as
ruthenium complexes. Therefore, we evaluated the
analgesic effect and mechanism of action of the
ruthenium nitric oxide donor [Ru(
HEDTA)NO] focusing on the role of
cytokines, oxidative stress and activation of the cyclic
guanosine monophosphate/
protein kinase G/
ATP-sensitive potassium channel signaling pathway. It was observed that [Ru(
HEDTA)NO] inhibited in a dose-dependent (1-10 mg/kg) manner the
acetic acid-induced writhing response. At the dose of 1 mg/kg, [Ru(
HEDTA)NO] inhibited the
phenyl-p-benzoquinone-induced writhing response, and
formalin- and complete
Freund's adjuvant-induced licking and flinching responses. Systemic and local treatments with [Ru(
HEDTA)NO] also inhibited the
carrageenin-induced
mechanical hyperalgesia and increase of
myeloperoxidase activity in paw skin samples. Mechanistically, [Ru(
HEDTA)NO] inhibited
carrageenin-induced production of the hyperalgesic
cytokines tumor necrosis factor-α and interleukin-1β, and decrease of
reduced glutathione levels. Furthermore, the inhibitory effect of [Ru(
HEDTA)NO] in the
carrageenin-induced
hyperalgesia and
myeloperoxidase activity was prevented by the treatment with ODQ (
soluble guanylyl cyclase inhibitor),
KT5823 (
protein kinase G inhibitor) and
glybenclamide (
ATP-sensitive potassium channel inhibitor), indicating that [Ru(
HEDTA)NO] inhibits inflammatory
hyperalgesia by activating the cyclic
guanosine monophosphate/
protein kinase G/
ATP-sensitive potassium channel signaling pathway, respectively. These results demonstrate that [Ru(
HEDTA)NO] exerts its
analgesic effect in
inflammation by inhibiting pro-nociceptive
cytokine production, oxidative imbalance and activation of the
nitric oxide/cyclic
guanosine monophosphate/
protein kinase G/
ATP-sensitive potassium channel signaling pathway in mice.