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

Year 2025, Volume: 55 Issue: 3, 411 - 418, 14.01.2026

Feyza Alyu Altınok , Abderaouf Boubekka , Ilhem Dallali , Ahmed Hasan , Muhammet Burak Açıkgül , Yusuf Burak , Yusuf Ozturk

https://doi.org/10.26650/IstanbulJPharm.2025.1704042

https://izlik.org/JA57ZW67LA

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

References

• Alyu Altinok, F., Dallali, I., Boubekka, A., Hasan, A., & Ozturk, Y. (2025). Optimized primary dorsal root ganglion cell culture protocol for reliable K+ current patchclamp recordings. Neuroscience Letters, 844, 138038. https://doi.org/10.1016/j.neulet.2024.138038
• Blaine, J. T., & Ribera, A. B. (2001). Kv2 channels form delayed-rectifier potassium channels in situ. Journal of Neuroscience, 21(5), 1473-1480. https://doi.org/10.1523/JNEUROSCI.21-05-1473.2001
• Callaghan, B. C., Price, R. S., Chen, K. S., & Feldman, E. L. (2015). The importance of rare subtypes in diagnosis and treatment of peripheral neuropathy: A review. JAMA Neurology, 72(12), 1510-1518. https://doi.org/10.1001/jamaneurol.2015.2347
• Chatterjea, D., Wetzel, A., Mack, M., Engblom, C., Allen, J., Mora-Solano, C., … & Martinov, T. (2012). Mast cell degranulation mediates compound 48/80-induced hyperalgesia in mice. Biochemical and Biophysical Research Communications, 425(2), 237-243. https://doi.org/10.1016/j.bbrc.2012.07.074
• Chaumette, T., Chapuy, E., Berrocoso, E., Llorca‐Torralba, M., Bravo, L., Mico, J. A., … & Sors, A. (2018). Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats. European Journal of Pain, 22(1), 127-141. https://doi.org/10.1002/ejp.1097
• Chen, K. H., Yang, C. H., Wallace, C. G., Lin, C. R., Liu, C. K., Yin, T. C., … & Yip, H. K. (2017). Combination therapy with extracorporeal shock wave and melatonin markedly attenuated neuropathic pain in rat. American Journal of Translational Research, 9(10), 4593-4606.
• Diaz, J. L., Zamanillo, D., Corbera, J., Baeyens, J. M., Maldonado, R., Pericàs, M. A., … & Torrens, A. (2009). Selective sigma-1 (sig1) receptor antagonists: Emerging target for the treatment of neuropathic pain. Central Nervous System Agents in Medicinal Chemistry, 9(3), 172-183. https://doi.org/10.2174/1871524910909030172
• Djouhri, L., Zeidan, A., Abd El-Aleem, S. A., & Smith, T. (2020). Cutaneous Aβnon-nociceptive, but not C-nociceptive, dorsal root ganglion neurons exhibit spontaneous activity in the streptozotocin rat model of painful diabetic neuropathy in vivo. Frontiers in Neuroscience, 14, 530. https://doi.org/10.3389/fnins.2020.00530
• Haas, H., & Panula, P. (2003). The role of histamine and the tuberomamillary nucleus in the nervous system. Nature Reviews Neuroscience, 4(2), 121-130. https://doi.org/10.1038/nrn1034
• Hasanein, P. (2011). Effects of histamine H3 receptors on chemical hyperalgesia in diabetic rats. Neuropharmacology, 60(6), 886-891. https://doi.org/10.1016/j.neuropharm.2011.01.004
• Mitterdorfer, J., & Bean, B. P. (2002). Potassium currents during the action potential of hippocampal CA3 neurons. Journal of Neuroscience, 22(23), 10106-10115. https://doi.org/10.1523/JNEUROSCI.22-23-10106.2002
• Neumann, D., Beermann, S., Burhenne, H., Glage, S., Hartwig, C., & Seifert, R. (2013). The dual H3/4R antagonist thioperamide does not fully mimic the effects of the ‘standard’H₄R antagonist JNJ 7777120 in experimental murine asthma. Naunyn-Schmiedeberg's Archives of Pharmacology, 386, 983-990. https://doi.org/10.1007/s00210-013-0898-4
• Obara, I., Telezhkin, V., Alrashdi, I., & Chazot, P. L. (2020). Histamine, histamine receptors, and neuropathic pain relief. British Journal of Pharmacology, 177(3), 580-599. https://doi.org/10.1111/bph.14696
• Parsons, M. E., & Ganellin, C. R. (2006). Histamine and its receptors. British Journal of Pharmacology, 147(S1), S127-S135. https://doi.org/10.1038/sj.bjp.0706440
• Pospisilik, J. A., Martin, J., Doty, T., Ehses, J. A., Pamir, N., Lynn, F. C., … & Pederson, R. A. (2003). Dipeptidyl peptidase IV inhibitor treatment stimulates β-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes, 52(3), 741-750. https://doi.org/10.2337/diabetes.52.3.741
• Rosa, A. C., & Fantozzi, R. (2013). The role of histamine in neurogenic inflammation. British Journal of Pharmacology, 170(1), 38-45. https://doi.org/10.1111/bph.12266
• Sah, P. & McLachlan, E. M. (1992). Potassium currents contributing to action potential repolarization and the afterhyperpolarization in rat vagal motoneurons. Journal of Neurophysiology, 68(5), 1834-1841. https://doi.org/10.1152/jn.1992.68.5.1834
• Spradley, J. M., Guindon, J., & Hohmann, A. G. (2010). Inhibitors of monoacylglycerol lipase, fatty-acid amide hydrolase and endocannabinoid transport differentially suppress capsaicin-induced behavioral sensitization through peripheral endocannabinoid mechanisms. Pharmacological Research, 62(3), 249-258. https://doi.org/10.1016/j.phrs.2010.03.007
• Üçel, U. İ., Can, Ö. D., Özkay, Ü. D., & Öztürk, Y. (2015). Antihyperalgesic and antiallodynic effects of mianserin on diabetic neuropathic pain: a study on mechanism of action. European Journal of Pharmacology, 756, 92-106. https://doi.org/10.1016/j.ejphar.2015.02.048
• Yan, J. E., Yuan, W., Lou, X., & Zhu, T. (2012). Streptozotocin-induced diabetic hyperalgesia in rats is associated with upregulation of Toll-like receptor 4 expression. Neuroscience Letters, 526(1), 54-58. https://doi.org/10.1016/j.neulet.2012.08.012