The neuronal potassium current I A is a potential target for pain during chronic inflammation.

Voltage-gated ion channels play a key role in the action potential (AP) initiation and its propagation in sensory neurons. Modulation of their activity during chronic inflammation creates a persistent pain state. In this study, we sought to determine how peripheral inflammation caused by complete Freund's adjuvant (CFA) alters the fast sodium (I _Na ), L-type calcium (I _CaL ), and potassium (I _K ) currents in primary afferent fibers to increase nociception. In our model, intraplantar administration of CFA induced mechanical allodynia and thermal hyperalgesia at day 14 post-injection. Using whole-cell patch-clamp recording in dissociated small (C), medium (Aδ), and large-sized (Aβ) rat dorsal root ganglion (DRG) neurons, we found that CFA prolonged the AP duration and increased the amplitude of the tetrodotoxin-resistant (TTX-r) I _Na in Aβ fibers. In addition, CFA accelerated the recovery of I _Na from inactivation in C and Aδ nociceptive fibers but enhanced the late sodium current (I _NaL ) only in Aδ and Aβ neurons. Inflammation similarly reduced the amplitude of I _CaL in each neuronal cell type. Fourteen days after injection, CFA reduced both components of I _K (I _Kdr and I _A ) in Aδ fibers. We also found that I _A was significantly larger in C and Aδ neurons in normal conditions and during chronic inflammation. Our data, therefore, suggest that targeting the transient potassium current I _A represents an efficient way to shift the balance toward antinociception during inflammation, since its activation will selectively decrease the AP duration in nociceptive fibers. Altogether, our data indicate that complex interactions between I _K , I _Na , and I _CaL reduce pain threshold by concomitantly enhancing the activity of nociceptive neurons and reducing the inhibitory action of Aβ fibers during chronic inflammation.
(© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)