M-type K+ channels in peripheral nociceptive pathways

Abstract

Pathological pain is a hyperexcitability disorder. Since the excitability of a neuron is set and controlled by a complement of ion channels it expresses, in order to understand and treat pain, we need to develop a mechanistic insight into the key ion channels controlling excitability within the mammalian pain pathways and how these ion channels are regulated and modulated in various physiological and pathophysiological settings. In this review, we will discuss the emerging data on the expression in pain pathways, functional role and modulation of a family of voltage-gated K⁺ channels called 'M channels' (KCNQ, K_v 7). M channels are increasingly recognized as important players in controlling pain signalling, especially within the peripheral somatosensory system. We will also discuss the therapeutic potential of M channels as analgesic drug targets.

Linked articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc/.

Figure 1

Role of M channels in sensory neurons from a biophysical perspective. (A) Schematized voltage‐dependence of an M channel (Kv7.2/Kv7.3) with relation to the resting membrane potential and firing threshold of a generalized C‐fibre nociceptor. Inset shows M currents recorded in a CHO cell, overexpressing K_v7.2 and K_v7.3, in response to the voltage steps depicted in the diagram above the traces. (B) Simulation of the effect of modulation of M channel (K_v7.2/K_v7.3) activity with an ‘opener’, retigabine and blocker, XE991, on steady‐state membrane potential. Steady‐state membrane potential (Vm) arises when net current across the plasma membrane is zero (in this example, for only ‘M’ and leak currents). Varying M channel voltage‐dependence and maximum conductance (G_M) shifts V_m (leak currents were kept constant). Parameters for V_rest, retigabine and XE991 were obtained from Linley et al. (2012b). (C) Current‐clamp recording of the effect of retigabine and XE991 on the V_m recorded from a cultured small‐diameter rat nociceptor in current‐clamp mode (modified from Du et al., 2014, with permission). (D) Effects of retigabine and XE991 on the firing threshold and frequency of a cultured small‐diameter mouse nociceptor; stimulus ramp is shown below the traces.

Figure 2

Simplified schematic of a nociceptive neuron. Dotted boxes encircle areas where functional M channel activity has been recorded in situ using slices (spinal cord, DRG) or skin‐nerve preparations. Examples of recordings from such preparations are also shown as follows: (a) the effects of retigabine and XE991 on heat‐induced Aδ fibre activity recorded in skin‐saphenous‐nerve preparation (modified from Passmore et al., 2012, with permission); (b) the effect of the same compounds on the resting membrane potential of a capsaicin‐sensitive neuron recorded from the DRG ‘slice’ using a sharp electrode recording (modified from Du et al., 2014, with permission); (c) the effect of flupirtine on the 4‐AP‐induced excitatory activity recorded extracellularly from substantia gelatinosa in rat spinal cord (modified from Visockis and King, 2013, with permission). Abbreviations: 4‐AP, 4‐aminopiridine; RTG, retigabine, SC, spinal cord.

Figure 3

Chemical structures of retigabine and its analogues.

Figure 4

Biophysical model of a small‐diameter unmyelinated DRG neuron. (A) Shown on the left is a drawing of soma and stem axon of small‐diameter cat DRG neuron (based on micrograph from Ha, 1970); on the right are the morphological dimensions of the model neuron. (B) Enhancing the activity of M channels with virtual retigabine (−30 mV shift in activation curve, 1.5 fold increase in conductance density) hyperpolarized the t‐junction and reduced (at initial I_M density of 0.9 pA/pF) or abolished (at initial I_M density of 1.05 pA/pF) spike propagation in the model neuron. (C) Retigabine reduces the likelihood of spike generation in the central axon. Action potential amplitude is plotted as function of distance along 100 μm of peripheral and central axon sections with the t‐junction in the middle. In control conditions, spike amplitude decreases when approaching the t‐junction, due to the impedance load of the bifurcation. On the central side of the t‐junction, a delayed action potential develops and grows with distance from the t‐junction. When retigabine is added, the spike amplitude in the peripheral axon is not significantly affected; in contrast, the spike fails on the central side of the t‐junction and its decay is recorded (modified from Du et al., 2014, with permission).