The protein tyrosine kinase inhibitor, genistein, decreases excitability of nociceptive neurons.

One mechanism by which neurons regulate their excitability is through ion channel phosphorylation. Compounds that increase nociceptive neuron excitability can cause hyperalgesia or allodynia whereas compounds that decrease nociceptive neuron excitability can be used as analgesics to relieve pain arising from inflammation or trauma. To identify targets that may cause a decrease in nociceptive neuron excitability, we have investigated the effects of genistein, a specific inhibitor of protein tyrosine kinases (PTKs), on capsaicin-sensitive neurons from cultured rat trigeminal ganglion neurons. It was found that genistein decreased the number of evoked action potentials, and hence their excitability. To determine whether genistein's effects occur through the inhibition of PTKs, we also tested the effects of two of its inactive analogues, daidzein and genistin. Whereas daidzein decreased excitability, albeit to a lower extent than genistein, excitability was unaffected by genistin. To determine which currents are involved in genistein's reduction in nociceptive neuron excitability, whole-cell voltage-clamp measurements were performed on voltage-gated sodium and potassium currents. One hundred micromolar genistein, daidzein and genistin inhibited tetrodotoxin-resistant voltage-gated sodium currents 74, 42, and 3%, respectively. Genistein markedly inhibited delayed rectifier (IK) and IA potassium currents, whereas daidzein and genistin were comparatively ineffective. In summary, we found that genistein's ability to inhibit nociceptive neuron excitability arises primarily from its non-specific inhibition of voltage-dependent sodium channels.