Molecular mechanisms and signaling by comenic acid in nociceptive neurons influence the pathophysiology of neuropathic pain

Valentina A Penniyaynen; Vera B Plakhova; Ilya V Rogachevskii; Stanislav G Terekhin; Svetlana A Podzorova; Boris V Krylov

doi:10.1016/j.pathophys.2019.06.003

Molecular mechanisms and signaling by comenic acid in nociceptive neurons influence the pathophysiology of neuropathic pain

Pathophysiology. 2019 Sep-Dec;26(3-4):245-252. doi: 10.1016/j.pathophys.2019.06.003. Epub 2019 Jun 13.

Authors

Valentina A Penniyaynen¹, Vera B Plakhova², Ilya V Rogachevskii³, Stanislav G Terekhin⁴, Svetlana A Podzorova⁵, Boris V Krylov⁶

Affiliations

¹ Laboratory of Physiology of Excitable Membranes, Pavlov Institute of Physiology of the Russian Academy of Sciences, 6 Nab. Makarova, 199034, Saint Petersburg, Russia. Electronic address: pvalentina2@yandex.ru.
² Laboratory of Physiology of Excitable Membranes, Pavlov Institute of Physiology of the Russian Academy of Sciences, 6 Nab. Makarova, 199034, Saint Petersburg, Russia. Electronic address: verapl@mail.ru.
³ Laboratory of Physiology of Excitable Membranes, Pavlov Institute of Physiology of the Russian Academy of Sciences, 6 Nab. Makarova, 199034, Saint Petersburg, Russia. Electronic address: roggie_spb_ru@yahoo.com.
⁴ Laboratory of Physiology of Excitable Membranes, Pavlov Institute of Physiology of the Russian Academy of Sciences, 6 Nab. Makarova, 199034, Saint Petersburg, Russia. Electronic address: stasok32@yandex.ru.
⁵ Laboratory of Physiology of Excitable Membranes, Pavlov Institute of Physiology of the Russian Academy of Sciences, 6 Nab. Makarova, 199034, Saint Petersburg, Russia. Electronic address: podzorova@infran.ru.
⁶ Laboratory of Physiology of Excitable Membranes, Pavlov Institute of Physiology of the Russian Academy of Sciences, 6 Nab. Makarova, 199034, Saint Petersburg, Russia. Electronic address: krylov@infran.ru.

PMID: 31257013
DOI: 10.1016/j.pathophys.2019.06.003

Abstract

Comenic acid (CA), a specific agonist of opioid-like receptors, effectively and safely relieves neuropathic pain by decreasing the Na_V1.8 channel voltage sensitivity in the primary sensory neuron membrane. CA triggers downstream signaling cascades, in which the Na,K-ATPase/Src complex plays a key role. After leaving the complex, the signal diverges 'tangentially' and 'radially'. It is directed 'tangentially' along the neuron membrane to Na_V1.8 channels, decreasing the effective charge of their activation gating system. In the radial direction moving towards the cell genome, the signal activates the downstream signaling pathway involving PKC and ERK1/2. A remarkable feature of CA is its ability to modulate Na_V1.8 channels, which relieves neuropathic pain while simultaneously stimulating neurite growth via the receptor-coupled activation of the ERK1/2-dependent signaling pathway.

Keywords: Comenic acid; Na(V)1.8 channels; Nociceptive neuron; Signaling cascade.