The neuronal potassium current IA 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 (A delta), and large-sized (A beta) 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 A beta fibers. In addition, CFA accelerated the recovery of I-Na from inactivation in C and A delta nociceptive fibers but enhanced the late sodium current (I-NaL) only in A delta and A beta 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 A delta fibers. We also found that I-A was significantly larger in C and A delta 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 A beta fibers during chronic inflammation.