H₃ Receptor Antagonism Reduces Macroscopic K⁺ Currents in a Voltage-Dependent Manner in Diabetic Rat DRG Neurons: Insights into Pain Regulation

Abstract

Background and aims: Diabetic neuropathy involves sensory neuron hyperexcitability. We examined how H₃ receptor antagonism affects total K⁺currents in dorsal root ganglion (DRG) neurons from streptozocin-induced diabetic rats. Methods: Neuropathy was confirmed by e-von Frey and Hargreave’s testing at 4 weeks post-injection. K+ currents were investigated using whole-cell patch-clamp recordings in the voltage-clamp mode. To activate the voltage-gated K+ channels, the neurons were held at −60 mV and subjected to a series of depolarising pulses from −60 mV up to +100 mV in 10 mV increments. Results: Acute application of thioperamide (100 μM) significantly reduced K⁺ currents in the depolarised voltage range of +30 to +100 mV, with p-values ranging from 0.0362 to 0.0031 (n = 13) and an increasing significance at higher voltages. In the conductance–voltage analysis, thioperamide was found to significantly alter the voltage dependence of channel activation, likely reducing the active channel numbers or their open probability. Conclusion: The voltage-dependent inhibition likely reflects the modulation of the high-voltage activated voltagegated K⁺ channels. The reduction in K⁺ currents can be paradoxically interpreted: decreased K⁺ conductance may enhance neuronal excitability by impairing repolarization but also prolong the action potential duration, potentially limiting immediate repetitive firing. Thioperamide increases histamine release by blocking H₃ autoreceptor, reducing neuroinflammation and producing analgesia despite its possible excitatory effects on DRG neurons. This highlights the dual peripheral and central roles of H₃ modulation in diabetic neuropathy. Future studies should explore the in vivo relevance of these ionic changes and their impact on pain behaviour.

Keywords

• Diabetic Neuropathy
• Dorsal Root Ganglion Neurons
• H₃ Receptor Antagonist
• Patch-Clamp Technique
• Potassium Currents

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