Loperamide inhibits sodium channels to alleviate inflammatory hyperalgesia

Ying Wu, Beiyan Zou, Lingli Liang, Min Li, Yuan Xiang Tao, Haibo Yu, Xiaoliang Wang, Min Li

Research output: Contribution to journalArticle

Abstract

Previous studies demonstrated that Loperamide, originally known as an anti-diarrheal drug, is a promising analgesic agent primarily targeting mu-opioid receptors. However some evidences suggested that non-opioid mechanisms may be contributing to its analgesic effect. In the present study, Loperamide was identified as a Nav1.7 blocker in a pilot screen. In HEK293 cells expressing Nav1.7 sodium channels, Loperamide blocked the resting state of Nav1.7 channels (IC50 = 1.86 ± 0.11 μM) dose-dependently and reversibly. Loperamide produced a 10.4 mV of hyperpolarizing shift for the steady-state inactivation of Nav1.7 channels without apparent effect on the voltage-dependent activation. The drug displayed a mild use- and state-dependent inhibition on Nav1.7 channels, which was removed by the local anesthetic-insensitive construct Nav1.7-F1737A. Inhibition of Nav1.7 at resting state was not altered significantly by the F1737A mutation. Compared to its effects on Nav1.7, Loperamide exhibited higher potency on recombinant Nav1.8 channels in ND7/23 cells (IC50 = 0.60 ± 0.10 μM) and weaker potency on Nav1.9 channels (3.48 ± 0.33 μM). Notably more pronounced inhibition was observed in the native Nav1.8 channels (0.11 ± 0.08 μM) in DRG neurons. Once mu-opioid receptor was antagonized by Naloxone in DRG neurons, potency of Loperamide on Nav1.8 was identical to that of recombinant Nav1.8 channels. The inhibition on Nav channels may be the main mechanism of Loperamide for pain relief beyond mu-opioid receptor. In the meanwhile, the opioid receptor pathway may also influence the blocking effect of Loperamide on sodium channels, implying a cross-talk between sodium channels and opioid receptors in pain processing.

Original languageEnglish (US)
Pages (from-to)282-291
Number of pages10
JournalNeuropharmacology
Volume117
DOIs
StatePublished - May 1 2017

Fingerprint

Loperamide
Sodium Channels
Hyperalgesia
mu Opioid Receptor
Diagnosis-Related Groups
Opioid Receptors
Inhibitory Concentration 50
Analgesics
Neurons
Pain
HEK293 Cells
Naloxone
Local Anesthetics
Pharmaceutical Preparations
Mutation
Inhibition (Psychology)

Keywords

  • Loperamide
  • Nav1.7
  • Opioid receptor
  • Pain
  • Sodium channel

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Wu, Y., Zou, B., Liang, L., Li, M., Tao, Y. X., Yu, H., ... Li, M. (2017). Loperamide inhibits sodium channels to alleviate inflammatory hyperalgesia. Neuropharmacology, 117, 282-291. https://doi.org/10.1016/j.neuropharm.2017.02.010

Loperamide inhibits sodium channels to alleviate inflammatory hyperalgesia. / Wu, Ying; Zou, Beiyan; Liang, Lingli; Li, Min; Tao, Yuan Xiang; Yu, Haibo; Wang, Xiaoliang; Li, Min.

In: Neuropharmacology, Vol. 117, 01.05.2017, p. 282-291.

Research output: Contribution to journalArticle

Wu, Y, Zou, B, Liang, L, Li, M, Tao, YX, Yu, H, Wang, X & Li, M 2017, 'Loperamide inhibits sodium channels to alleviate inflammatory hyperalgesia', Neuropharmacology, vol. 117, pp. 282-291. https://doi.org/10.1016/j.neuropharm.2017.02.010
Wu, Ying ; Zou, Beiyan ; Liang, Lingli ; Li, Min ; Tao, Yuan Xiang ; Yu, Haibo ; Wang, Xiaoliang ; Li, Min. / Loperamide inhibits sodium channels to alleviate inflammatory hyperalgesia. In: Neuropharmacology. 2017 ; Vol. 117. pp. 282-291.
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