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.
Highlights
Neuropathic pain is a source of intractable chronic pain in conditions such as cancer, fibromyalgia, diabetic neuropathy and postherpetic neuralgia
We have previously shown that the purinergic receptor P2X4 (P2X4R), a subtype of adenosine 5’-triphosphate disodium salt (ATP)-gated non-selective cation channels, is highly upregulated in spinal microglia after peripheral nerve injury (PNI), and blocking the function of the P2X4 receptors (P2X4R) produces a reversal of mechanical allodynia [4]
We identified the SNRI duloxetine as a compound that has an inhibitory effect on ATP-induced increases in [Ca2+]i, and that is known to possess both oral availability and the ability to cross the blood-brain barrier
Summary
Neuropathic pain is a source of intractable chronic pain in conditions such as cancer, fibromyalgia, diabetic neuropathy and postherpetic neuralgia. A prominent symptom is abnormal pain hypersensitivity evoked by normally innocuous stimuli, known as mechanical allodynia. Analgesics such as pregabalin and opioids are used for treating neuropathic pain, it has been estimated that only one in four patients experiences over 50% pain relief [1]. The clinical use of these drugs is often limited by side effects such as dizziness, obstipation.
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