Duloxetine inhibits microglial P2X4 receptor function and alleviates neuropathic pain after peripheral nerve injury

Tomohiro Yamashita, Shota Yamamoto, Jiaming Zhang, Miho Kometani, Daisuke Tomiyama, Keita Kohno, Hidetoshi Saitoh, Kazuhide Inoue, Tsuda Makoto

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

P2X4 receptors (P2X4R) are a family of ATP-gated non-selective cation channels. We previously demonstrated that activation of P2X4R in spinal microglia is crucial for neuropathic pain, a highly debilitating chronic pain condition, suggesting that P2X4R is a potential therapeutic target for treating neuropathic pain. Thus, the identification of a compound that has a potent inhibitory effect on P2X4R is an important clinical challenge. In the present study, we screened a chemical library of clinically approved drugs and show for the first time that duloxetine, a serotonin and noradrenaline reuptake inhibitor, has an inhibitory effect on rodent and human P2X4R. In primary cultured microglial cells, duloxetine also inhibited P2X4R-, but not P2X7R-, mediated responses. Moreover, intrathecal administration of duloxetine in a model of neuropathic pain produced a reversal of nerve injury-induced mechanical allodynia, a cardinal symptom of neuropathic pain. In rats that were pretreated with a serotonin-depleting agent and a noradrenaline neurotoxin, the antiallodynic effect of duloxetine was reduced, but still remained. Based on these results, we suggest that, in addition to duloxetine's primary inhibitory action on serotonin and noradrenaline transporters, an inhibitory effect on P2X4R may be involved at least in part in an antiallodynic effect of intrathecal duloxetine in a model of neuropathic pain.

Original languageEnglish
Article numbere0165189
JournalPloS one
Volume11
Issue number10
DOIs
Publication statusPublished - Oct 1 2016

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Purinergic P2X4 Receptors
Peripheral Nerve Injuries
peripheral nerves
Neuralgia
pain
receptors
norepinephrine
serotonin
Norepinephrine Plasma Membrane Transport Proteins
Small Molecule Libraries
Serotonin Agents
Serotonin Plasma Membrane Transport Proteins
neurotoxins
Hyperalgesia
Neurotoxins
neuroglia
Microglia
Duloxetine Hydrochloride
Chronic Pain
cultured cells

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Duloxetine inhibits microglial P2X4 receptor function and alleviates neuropathic pain after peripheral nerve injury. / Yamashita, Tomohiro; Yamamoto, Shota; Zhang, Jiaming; Kometani, Miho; Tomiyama, Daisuke; Kohno, Keita; Saitoh, Hidetoshi; Inoue, Kazuhide; Makoto, Tsuda.

In: PloS one, Vol. 11, No. 10, e0165189, 01.10.2016.

Research output: Contribution to journalArticle

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