Combinations of classical and non-classical voltage dependent potassium channel openers suppress nociceptor discharge and reverse chronic pain signs in a rat model of Gulf War illness

Neurotoxicology. 2022 Dec:93:186-199. doi: 10.1016/j.neuro.2022.10.003. Epub 2022 Oct 8.

Abstract

In a companion paper we examined whether combinations of Kv7 channel openers (Retigabine and Diclofenac; RET, DIC) could be effective modifiers of deep tissue nociceptor activity; and whether such combinations could then be optimized for use as safe analgesics for pain-like signs that developed in a rat model of GWI (Gulf War Illness) pain. In the present report, we examined the combinations of Retigabine/Meclofenamate (RET/MEC) and Meclofenamate/Diclofenac (MEC/DIC). Voltage clamp experiments were performed on deep tissue nociceptors isolated from rat DRG (dorsal root ganglion). In voltage clamp studies, a stepped voltage protocol was applied (-55 to -40 mV; Vh=-60 mV; 1500 msec) and Kv7 evoked currents were subsequently isolated by Linopirdine subtraction. MEC greatly enhanced voltage dependent conductance and produced exceptional maximum sustained currents of 6.01 ± 0.26 pA/pF (EC50: 62.2 ± 8.99 μM). Combinations of RET/MEC, and MEC/DIC substantially amplified resting currents at low concentrations. MEC/DIC also greatly improved voltage dependent conductance. In current clamp experiments, a cholinergic challenge test (Oxotremorine-M, 10 μM; OXO), associated with our GWI rat model, produced powerful action potential (AP) bursts (85 APs). Optimized combinations of RET/MEC (5 and 0.5 μM) and MEC/DIC (0.5 and 2.5 μM) significantly reduced AP discharges to 3 and 7 Aps, respectively. Treatment of pain-like ambulatory behavior in our rat model with a RET/MEC combination (5 and 0.5 mg/kg) successfully rescued ambulation deficits, but could not be fully separated from the effect of RET alone. Further development of this approach is recommended.

Keywords: Chronic pain; Diclofenac; Gulf War Illness; K(v)7; Meclofenamate; Retigabine.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Chronic Pain*
  • Diclofenac / pharmacology
  • Ganglia, Spinal
  • Meclofenamic Acid / pharmacology
  • Nociceptors
  • Persian Gulf Syndrome*
  • Potassium Channels
  • Rats

Substances

  • Diclofenac
  • ezogabine
  • Meclofenamic Acid
  • Potassium Channels