Physical pain is an essential part of human lives; it informs us when something in the body has gone wrong and distances people from dangerous situations. Although pain plays an important role in human lives, there exist various conditions which prevent individuals from sensing physical pain. One of these disorders, known as Congenital Insensitivity to Pain (CIP) has been tied to a loss-of-function mutation in the SCN9A gene which encodes for the NaV1.7 voltage-gated sodium channel (Li et al. 2016). A gain-of-function mutation in the same gene was tied to Inherited Erythromelalgia (IEM), a condition that makes people experience excruciating pain in response to mild heat and skin agitation. The connections made between these two disorders and the SCN9A gene confirmed a link between the sodium channel, NaV1.7, and the ability to feel physical pain (The Scientist, 2018). Currently, various research endeavors are being conducted to discover treatments for those with chronic pain syndromes by inhibiting NaV1.7 channels.
Neurons are responsible for receiving and transporting electrical signals throughout the body. The electrical signals receive ‘electrical boosts’ to prevent them from weakening as they travel along the neuronal axons. The electrically reinforced signals are known as action potentials. Action potentials are generated when an influx of positive sodium (Na) ions flow into a neuron, increasing its electrical potential beyond a certain threshold; this process of making a cell’s interior is known as depolarization. The sodium ions entering the neurons further depolarizes the plasma membrane causing more sodium channels to open. This cycle continues until the cell’s membrane potential increases from its resting value of -70mV to ~ +30mV. At this point, the sodium channels switch to an inactive state to prevent the flow of ions into the neuron and voltage-gated potassium channels open to restore the -70mV resting potential by allowing potassium ions to flow out of the cell (Alberts et al. 2014). Thus, pain signals, as well as other physiological signals, travel throughout the body in this manner. In this case, the pain signal is transported from the part of the body experiencing pain, to the spinal cord and then to the brain to be decoded.
The discovery of the connection between NaV1.7channels and pain was a crucial step in developing new treatments for those with chronic pain, however, NaV1.7 channels still pose many challenges scientists must overcome to effectively treat chronic pain conditions. For example, NaV1.7 is a member of the NaV protein family. Members of the NaV protein family are structurally similar as they consist of four voltage-sensitive transmembrane domains which envelop an opening through which ions enter the neuron. These openings have been highly conserved throughout the evolution of the protein-making them virtually identical among members of the NaV family; the similarity of these pores makes it difficult to find molecules that specifically target NaV1.7. Despite the NaV family members sharing a common pore, they each possess differing roles in various biological processes. For instance, one could end up with partial paralysis if NaV1.4 channels in muscle tissue were obstructed or could experience an irregular heartbeat if NaV1.5 channels in heart tissue were obstructed. These are some of the problems scientists must solve concerning NaV1.7channels (The Scientist, 2018).
Instead of trying to block off the highly conserved central opening, some scientists have focused their attention to the less conserved transmembrane domains surrounding the opening. Some success has been found using peptides from arthropod venom as they function to inhibit the process that activates the channels, certain spider venoms have even been found to bind one of the NaV1.7 domains which inactivate the channel. Many companies have been trying to manipulate the peptides from these venoms to specifically inactivate NaV1.7channels regardless of voltage changes. Studies have found that these peptides show high selectivity for NaV1.7 over other members of the NaV family and they have been found to significantly repress pain in mice (The Scientist, 2018).
There are thousands of people around the world that deal with chronic pain and very few of them have therapies that help their situation without any unpleasant side effects. Studies conducted on individuals with CIP and IEM led to the discovery of a link between NaV1.7channels and pain. Researchers are now making strides to create treatments that provide pain relief for those who suffer from chronic pain conditions by finding molecules that inhibit NaV1.7channels.
Alberts B, Johnson A, Lewis J, Morgan D, Raff M, et al. 2014. Molecular biology of the cell. Garland Science, New York, pp. 620-629. [textbook, tertiary literature]
Li Y, North RY, Rhines LD, Tatsui CE, Rao G, et al. 2018. DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain. The Journal of Neuroscience. 38:1124–1136. [primary literature, journal paper]
Offord C. Targeting Sodium Channels for Pain Relief. The Scientist, Jan. 1 2018. [magazine, popular literature]