Tetrodotoxin (TTX) as a therapeutic agent for pain

Abstract

Tetrodotoxin (TTX) is a potent neurotoxin that blocks voltage-gated sodium channels (VGSCs). VGSCs play a critical role in neuronal function under both physiological and pathological conditions. TTX has been extensively used to functionally characterize VGSCs, which can be classified as TTX-sensitive or TTX-resistant channels according to their sensitivity to this toxin. Alterations in the expression and/or function of some specific TTX-sensitive VGSCs have been implicated in a number of chronic pain conditions. The administration of TTX at doses below those that interfere with the generation and conduction of action potentials in normal (non-injured) nerves has been used in humans and experimental animals under different pain conditions. These data indicate a role for TTX as a potential therapeutic agent for pain. This review focuses on the preclinical and clinical evidence supporting a potential analgesic role for TTX. In addition, the contribution of specific TTX-sensitive VGSCs to pain is reviewed.

Keywords: TTX; TTX-sensitive voltage-gated sodium channels; neuropathic pain; pain; tetrodotoxin.

Figure 1

Schematic representation of voltage-gated sodium channel α-subunits and Tetrodotoxin (TTX) binding site. Voltage-gated sodium channel α-subunits are formed by four homologous domains (DI-IV), each consisting of 6 α-helical transmembrane segments (1–6). Segment 4 (dark red) corresponds to the voltage sensors. Sites of phosphorylation by protein kinase A (PKA) and protein kinase C (PKC) are represented by yellow circles and brown squares, respectively. The fast inactivation gate (IFM motif) is located in the intracellular loop between domains 3 and 4 and is represented by h (in pink oval); pink circles show the sites involved in forming the inactivation gate receptor. P-loops are located between helices 5 and 6 (in blue), which are the pore-lining segments (as shown in the lower figure). Outer (EEDD motif) and inner (DEKA motif) rings, represented by a green and purple band, respectively (in both the upper and lower figures), are formed by the amino acids indicated by circles of the same color. The TTX molecule interacts with the amino acid residues of these two rings in the pore of the channel, as detailed in the lower figure.

Figure 2

Proposed mechanism of action of TTX in sensory neurons during neuropathic pain. During neuropathy sensory neurons can produce ectopic action potentials, purportedly by the re-expression of the voltage-gated sodium channel (VGSC) Na_v1.3. The action potential is propagated along the axon to activate voltage-gated calcium channels (VGCCs), which in turn trigger the release of neurotransmitters by the presynaptic terminal to activate their receptors in dorsal horn neurons. TTX by inactivating TTX-sensitive sodium channels such as Na_v1.3, could prevent neuronal ectopic activity.

Figure 3

Schematic representation of the main evidences and conclusions obtained in preclinical and clinical human studies using TTX as a potential therapeutic agent for pain.