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Papers of the Week


Papers: 1 Oct 2022 - 7 Oct 2022


Animal Studies


2022 Sep 28


Neurosci Lett

NS5806 inhibits ERK activation to attenuate pain induced by peripheral nerve injury.

Authors

Chiu C-Y, Tsaur M-L
Neurosci Lett. 2022 Sep 28:136890.
PMID: 36181963.

Abstract

Neuropathic pain is a serious health problem, but optimal drug treatments remain lacking. It has been known that the compound NS5806 is a Kv4.3 activator, which increases Kv4.3-mediated K current to reduce neuronal excitability. In this study, we investigated the molecular and cellular mechanisms underlying the analgesic effect of NS5806 in neuropathic pain induced by peripheral nerve injury. Using lumbar (L)5/L6 spinal nerve ligation (SNL) in rats, we found that, without changing the basal nociception, the analgesic effect of NS5806 (220 μg/kg) peaked at 4 hours and lasted for 8 hours after intraperitoneal injection. Multiple doses of NS5806 reduced not only SNL-upregulated proinflammatory mediators in the DRG and spinal cord on day 1 and day 4 after L5/L6 SNL, but also SNL-evoked expansion of DRG macrophages and spinal microglia on day 4. Furthermore, at 10 minutes after L5 SNL, NS5806 pretreatment for 4 hours suppressed SNL-induced phosphorylated extracellular signal-regulated kinase (pERK) in both Kv4.3 and Kv4.3 neurons in the dorsal root ganglion (DRG) and superficial spinal dorsal horn, indicating that the action of NS5806 is not restricted to Kv4.3 neurons. In vitro kinase activity assays revealed that NS5806 weakly inhibited ERK2, MEK1, MEK2, and c-Raf in the ERK pathway. Since NS5806 and the ERK pathway inhibitors have similar antinociceptive characteristics, this study suggests that NS5806 also acts as an ERK pathway inhibitor to attenuate neuropathic pain.