Tetrodotoxin: A New Strategy to Treat Visceral Pain?

Abstract

Visceral pain is one of the most common symptoms associated with functional gastrointestinal (GI) disorders. Although the origin of these symptoms has not been clearly defined, the implication of both the central and peripheral nervous systems in visceral hypersensitivity is well established. The role of several pathways in visceral nociception has been explored, as well as the influence of specific receptors on afferent neurons, such as voltage-gated sodium channels (VGSCs). VGSCs initiate action potentials and dysfunction of these channels has recently been associated with painful GI conditions. Current treatments for visceral pain generally involve opioid based drugs, which are associated with important side-effects and a loss of effectiveness or tolerance. Hence, efforts have been intensified to find new, more effective and longer-lasting therapies. The implication of VGSCs in visceral hypersensitivity has drawn attention to tetrodotoxin (TTX), a relatively selective sodium channel blocker, as a possible and promising molecule to treat visceral pain and related diseases. As such, here we will review the latest information regarding this toxin that is relevant to the treatment of visceral pain and the possible advantages that it may offer relative to other treatments, alone or in combination.

Keywords: VGSCs; tetrodotoxin; visceral pain.

Figure 1

Scheme representing the primary sensory innervation of the gastrointestinal tract. The vagus nerve (green) has its cell bodies in the nodose ganglion (NG). Extrinsic primary afferent neurons (visceral afferent, in black) located in thoracolumbar and sacral dorsal root ganglion (DRG) and spinal fibers innervate the viscera and drive stimuli to the central nervous system. Furthermore, an intrinsic nervous system, the enteric nervous system (ENS, red) locally innervates the gastrointestinal tract.

Figure 2

Mechanism proposed for the blockade of tetrodotoxin (TTX) sensitive voltage-gated sodium channels (VGSCs) to diminish pain transduction in primary sensory neurons. (a) After a noxious stimulus reaches the depolarization threshold, TTX-sensitive and -resistant VGSCs are activated, generating action potentials (APs) along the axon to the presynaptic terminal. Here, neurotransmitter release activates the postsynaptic neuron, and the stimulus is transmitted to the central nervous system, evoking pain sensations. (b) By blocking TTX-sensitive VGSCs with TTX, AP transmission is dampened and consequently, painful sensations decrease.