Recent developments regarding voltage-gated sodium channel blockers for the treatment of inherited and acquired neuropathic pain syndromes

Abstract

Chronic and neuropathic pain constitute significant health problems affecting millions of individuals each year. Pain sensations typically originate in sensory neurons of the peripheral nervous system which relay information to the central nervous system (CNS). Pathological pain sensations can arise as result of changes in excitability of these peripheral sensory neurons. Voltage-gated sodium channels are key determinants regulating action potential generation and propagation; thus, changes in sodium channel function can have profound effects on neuronal excitability and pain signaling. At present, most of the clinically available sodium channel blockers used to treat pain are non-selective across sodium channel isoforms and can contribute to cardio-toxicity, motor impairments, and CNS side effects. Numerous strides have been made over the last decade in an effort to develop more selective and efficacious sodium channel blockers to treat pain. The purpose of this review is to highlight some of the more recent developments put forth by research universities and pharmaceutical companies alike in the pursuit of developing more targeted sodium channel therapies for the treatment of a variety of neuropathic pain conditions.

Keywords: Nav1.7; Nav1.8; TRPV1; neuropathic pain; resurgent currents; voltage-gated sodium channel.

Figure 1

Nav1.7 mutations associated with inherited pain syndromes. A linear representation of the Nav1.7 α-subunit showing the approximate mutation sites for CIP, congenital insensitivity to pain; IEM, inherited erythromelalgia; PEPD, paroxysmal extreme pain disorder.

Figure 2

Transient receptor potential vanilloid 1 and QX-314: No pain, no gain. Due to its positive charge, the lidocaine derivative QX-314 is unable to pass through the plasma membrane to gain access to its binding site on the intracellular face of the sodium channel pore. Activation of TRPV1 by capsaicin (the pungent ingredient in chili peppers) allows QX-314 to pass through the relatively large pore of TRPV1, shuttling QX-314 into the cytosol where it can bind and inhibit the sodium channel. TRPV1 receptors are preferentially expressed on nociceptive terminals thus allowing selective inhibition of pain-transmitting nerve fibers.

Figure 3

Lacosamide enhances sodium channel slow-inactivation without altering fast inactivation. (A) Carbamazepine, but not lacosamide, enhances Nav1.7 fast inactivation as evident by a hyperpolarizing shift in the voltage-dependence of steady-state fast inactivation. (B) Lacosamide, but not carbamazepine, causes a significant shift in the voltage-dependence of Nav1.7 slow-inactivation. (C,E) Pulse protocols for determining the voltage-dependence of fast and slow-inactivation, respectively. (D) A simplified diagram showing the different channel occupancy states, where C indicates the closed-state, O the open state, FI the fast-inactivated state and SI the slow-inactivated state. (A,B) adapted from Sheets et al. ( with permission from The Journal of Pharmacology and Experimental Therapeutics.

Figure 4

Resurgent sodium currents. (A) Following a strong depolarization, sodium channels transition from the resting closed-state to open, allowing influx of sodium. Within milliseconds, the channel inactivates via a hinged-lid mechanism and remains inactivated until the membrane potential has been sufficiently hyperpolarized. This cycle of events underlies the action potential refractory period. (B) Following a strong depolarization, a blocking particle (likely the C-terminal portion of the auxiliary Navβ4 subunit) can occlude the open-channel before the inactivation gate can bind, thus resulting in open-channel block. Following a hyperpolarization to an intermediate potential, the blocker is expelled resulting in an additional surge in current. (C) Representative resurgent sodium currents recorded from a large Nav1.8-null DRG neuron. The traces are magnified in the right panel to better see the resurgent currents. (D) The voltage-dependence of the resurgent currents is shown by plotting the peak resurgent current amplitude against the repolarization pulse potential. (C,D) adapted from Cummins et al. 2005) with permission from FEBS Letters.