Nitroxyl inhibits overt pain-like behavior in mice: Role of cGMP/PKG/ATP-sensitive potassium channel signaling pathway

Abstract

Background Several lines of evidence have indicated that nitric oxide (NO) plays complex and diverse roles in modulation of pain/analgesia. However, the roles of charged and uncharged congeners of NO are less well understood. In the present study, the antinociceptive effect of the nitroxyl (HNO) donor, Angeli’s salt (Na2N2O3; AS) was investigated in models of overt pain-like behavior. Moreover, whether the antinociceptive effect of nitroxyl was dependent on the activation of cGMP (cyclic guanosine monophosphate)/PKG (protein kinase G)/ATP-sensitive potassium channels was addressed. Methods The antinociceptive effect of AS was evaluated on phenyl-p-benzoquinone (PBQ)- and acetic acid-induced writhings and via the formalin test. In addition, pharmacological treatments targeting guanylate cyclase (ODQ), PKG (KT5923) and ATP-sensitive potassium channel (glybenclamide) were used. Results PBQ and acetic acid induced significant writhing responses over 20 min. The nociceptive response in these models were significantly reduced in a dose-dependent manner by subcutaneous pre-treatment with AS. Furthermore, AS also inhibited both phases of the formalin test. Subsequently, the inhibitory effect of AS in writhing and flinching responses were prevented by ODQ, KT5823 and glybenclamide, although these inhibitors alone did not alter the writhing score. Furthermore, pretreatment with L-cysteine, an HNO scavenger, confirmed that the antinociceptive effect of AS depends on HNO. Conclusion The present study demonstrates the efficacy of a nitroxyl donor and its analgesic mechanisms in overt pain-like behavior by activating the cGMP/PKG/ATP-sensitive potassium channel (K+) signaling pathway.

The nitroxyl donor, Angeli’s salt, reduces chronic constriction injury-induced neuropathic pain

“…Nitroxyl is capable of activating sGC to produce cGMP in other systems [22–24]. In agreement with the AS-induced activation of sGC, AS reduces acute inflammatory pain by activating the cGMP/PKG/ATP-sensitive potassium channels signaling pathway [25,26]. Notwithstanding, there are conflicting literature data showing that the activation of cGMP mediates hyperalgesia in neuropathic pain models [47,48].…”

“…For instance, nitroxyl can activate soluble guanylate cyclase (sGC), a primary NO target [21–24]. As such, the nitroxyl donor, Angeli’s salt (Na 2 N 2 O 3 ; AS), reduces inflammatory hyperalgesia and spontaneous overt pain-like behavior by activating the cGMP/PKG/ATP-sensitive potassium channels[25,26]. The analgesic effect of AS depends on nitroxyl since it was inhibited by L-cysteine (a nitroxyl scavenger) [25,26].…”

“…AS significantly reduces the acute inflammatory hyperalgesia induced by carrageenan, lipopolysaccharide (LPS), TNF-α, IL-1β, and prostaglandin E 2 as well as diminishes the overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone and formalin [25,26]. However, it is not known whether AS exerts analgesic activity capable of controlling neuropathic pain.…”

A Chemiluminescent Probe for HNO Quantification and Real‐Time Monitoring in Living Cells

“…[6] While both HNO and NO can activate soluble guanylyl cyclase,only HNO acts apositive cardiac inotrope by direct reaction with cysteine residues on cardiac ryanodine receptors and the sarcoplasmic reticulum Ca 2+ -ATPase (SERCA2a). [8] HNO derived from Angeliss alt (Na 2 N 2 O 3 )r educes pain in animal models through ac GMP/PKG/K ATP pathway [9] and HNO derived from oxidative metabolism of cyanamide has been used clinically as adeterrent for alcohol consumption by inhibiting aldehyde dehydrogenase. [8] HNO derived from Angeliss alt (Na 2 N 2 O 3 )r educes pain in animal models through ac GMP/PKG/K ATP pathway [9] and HNO derived from oxidative metabolism of cyanamide has been used clinically as adeterrent for alcohol consumption by inhibiting aldehyde dehydrogenase.…”

“…[7] Additionally,c ontinued use does not lead to tolerance,acritical issue with organic nitrate NO donors. [8] HNO derived from Angeliss alt (Na 2 N 2 O 3 )r educes pain in animal models through ac GMP/PKG/K ATP pathway [9] and HNO derived from oxidative metabolism of cyanamide has been used clinically as adeterrent for alcohol consumption by inhibiting aldehyde dehydrogenase. [10] Early attempts at using Angelis salt (Na 2 N 2 O 3 )a nd other HNO donors in the clinic were hampered by short half-lives,poor pharmacokinetics,and byproducts.…”