HYP-17, a novel voltage-gated sodium channel blocker, relieves inflammatory and neuropathic pain in rats

HYP-17, a novel voltage-gated sodium channel blocker, relieves inflammatory and neuropathic pain in rats
윤인찬한성민Jee Youn LeeYoo Lim KamJungae OhDong Hyun KimJin-Sung ChoiHea Young ChoiHea-Young Park ChooTae Young Yune
HYP-17; voltage-gated sodium channel blocker; pain; Sodium channel inhibitor; Spinal cord injury; Tail nerve injury; Neuropathic pain; Microglia; Astrocyte
Issue Date
Pharmacology, biochemistry and behavior
VOL 153-129
Clinical and experimental studies suggest that voltage-gated sodium channels (VGSCs) play a key role in the pathogenesis of neuropathic pain and that blocking agents against these channels can be potentially therapeutic. In the current study, we investigated whether a novel compound, (-)-2-Amino-1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-propan-1-one(HYP-17), binds to VGSCs and evaluated its inhibitory effect on Na+ currents of the rat dorsal root ganglia (DRG) sensory neurons and its analgesic effect on inflammatory and neuropathic pain. HYP-17 (10 μM) reduced both the tetrodotoxin-sensitive (TTX-S) and the TTX-resistant (TTX-R) currents in DRG sensory neurons. However, neither the voltage-dependent activation curves nor the steady-state inactivation curves for TTX-S and TTX-R currents were changed by HYP-17. In rats injected with 5% formalin under the plantar surface of the hind paw, HYP-17 (10 μg) significantly reduced both the early and late phase spontaneous pain behaviors. Systemic injection with HYP-17 (60 mg/kg, i.p.) also significantly relieved the mechanical, cold, and warm allodynia induced by rat tail nerve injury. Furthermore, HYP-17 (60 mg/kg, i.p.) significantly relieved the central neuropathic pain induced by spinal cord injury (SCI), and inhibited c-Fos expression in lumbar (L) 4– L5 spinal segments. Electrophysiological study showed that HYP-17 significantly attenuated the hyper-responsiveness of lumbar dorsal horn neurons. In addition, HYP-17 significantly reduced the levels of pp38MAPK and p-JNK in microglia and astrocytes, respectively, in the L4-L5 spinal dorsal horn. Therefore, our results indicate that HYP-17 has potential analgesic activities against nociceptive, inflammatory and neuropathic pain.
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