Pain is an important warning system. When we touch something hot or experience an injury, specialised nerve cells detect the potentially harmful stimulus and send signals to the brain, allowing us to respond.

For people with neuropathic pain, this system does not always work as it should. Neuropathic pain occurs when damage or changes to the nervous system cause abnormal pain signalling. As a result, everyday sensations such as light touch or pressure can become painful, while pain can sometimes occur without an obvious trigger.

Although several medicines are available to treat neuropathic pain, they do not work for everyone and can cause unwanted side effects. Researchers are therefore investigating new ways to target the biological processes responsible for pain.

One promising target is a protein called Nav1.7. Located in the membrane of nerve cells, they help generate the electrical signals involved in detecting and transmitting pain.

A recent study published in the Open Access journal Pharmaceutics investigated whether antibodies designed to target Nav1.7 could reduce neuropathic pain. The researchers found that their antibodies reduced pain-related behaviour in rats and remained effective for at least 96 hours after a single dose. Dr. Daisuke Uta, corresponding author of the study, highlights the potential of the work:

Targeting Nav1.7 could help silence abnormal pain signals while preserving normal protective pain sensation.

Importantly, one of the antibodies studied is currently being tested in clinical trials in humans. This highlights the potential of antibody therapeutics in medicine.

What is neuropathic pain?

The nervous system is responsible for communicating information between the brain and the rest of the body. This includes information about potentially harmful stimuli, such as extreme temperatures, pressure, or tissue damage.

Specialised nerve cells called nociceptors detect these potentially harmful stimuli. They then send electrical signals through the nervous system, allowing the brain to recognise and respond to the pain.

Neuropathic pain is different and occurs when nerve cells become damaged or become abnormally sensitive. This can cause the nervous system to send pain signals too easily which can cause a person to experience either:

• Allodynia: pain from a stimulus that would not normally be painful.
• Hyperalgesia: an exaggerated response to a painful stimulus.
• Plus, a range of other pain related symptoms.

It is estimated that 60% of patients with neuropathic pain may also experience anxiety and depression, highlighting the importance of finding new approaches to treat this condition.

The role of Nav1.7 in pain

Nav1.7 is a voltage-gated sodium channel (VGSC), a tunnel-like protein that exists in the membrane of nerve cells. Its channel opens in response to a change in local voltage allowing sodium ions to cross the membrane. This process itself causes a further change in voltage which opens other channels along the membrane and allows the transfer of information along a nerve cell from stimulus to brain or vice versa.

In particular, Nav1.7 is important in sensory neurons which are involved in detecting pain. This has been proven in human genetic studies which show that mutations to this protein can have very different effects on pain perception.

These observations have made Nav1.7 an attractive target for pain treatments. If its activity could be reduced in people experiencing neuropathic pain, it might be possible to reduce abnormal pain signalling.

However, developing drugs that selectively target Nav1.7 has proved challenging.

Developing novel therapies to target Nav1.7

Nav1.7 is one member of a larger family of VGSCs. These proteins are structurally similar but perform different roles throughout the body.

This similarity can make it difficult to develop small molecule drugs to target Nav1.7 without also interacting with other VGSCs, leading to potential unwanted side effects.

Antibodies are proteins produced naturally by the immune system. They recognise specific molecules, known as antigens, and bind to them. This highly specific recognition is useful in medicine, where antibodies can be designed to target particular proteins involved in disease.

The researchers developed monoclonal antibodies against Nav1.7. Desirable antibodies should have high selectivity to Nav1.7 while demonstrating prolonged efficacy.

The researchers first tested whether the antibodies could selectively recognise Nav1.7 using enzyme-linked immunosorbent assays (ELISA). They designed two antibodies, named Clone1 and S-151128, which bound strongly to Nav1.7 but not to other sodium channel subtypes. Clone1 was at least 650-times more selective while S-151128 was at least 1300-times more selective.

They then tested the antibodies’ ability to bind to Nav1.7 in the cell membrane using HEK cells displaying the protein. Fluorescent staining revealed that both antibodies were capable of this, supporting their ability to recognise the channel in a cellular environment (Figure 1).

Figure 1: Immunofluorescent staining of HEK cells containing Human Nav1.7 by the designed antibodies. The negative control contains cells incubated without the primary antibody, leading to little staining.

Reducing the activity of pain-sensing neurons

The researchers tested the antibodies using the HEK cells containing the Nav1.7 protein and measured the electrical current produced when the channel was active.

Both antibodies reduced the sodium currents passing through Nav1.7, suggesting that they could inhibit the channel.

Subsequent experiments tested the antibodies in sensory neurons taken from rats that are involved in detecting and transmitting pain. Both antibodies reduced the activity of these neurons, highlighting the ability to interfere with the electrical activity associated with pain signalling through binding to Nav1.7.

Testing the antibodies’ effects on pain in vivo

Initially, the researchers assessed the antibodies’ effect on neuropathic pain in rats with damaged sciatic nerves. Paw withdrawal threshold is the amount of force required to make an animal withdraw its paw from a stimulus. A lower threshold indicates increased sensitivity to touch, while an increased threshold suggests reduced pain sensitivity.

Both Clone1 and S-151128 increased the paw withdrawal threshold when administered to affected rats, implying that the animals had become less sensitive to pain with the effect of the pain being dependent on the dose administered.

In addition to this, the antibodies were shown to still demonstrate a reduction in neuropathic pain 96 hours after the initial treatment. This long-lasting effect is an advantage of antibody therapeutics which can remain biologically active for longer than small drug molecules.

Understanding the effects of antibody therapeutics on pain signalling

While reducing pain can be beneficial, completely removing the ability to detect potentially harmful stimuli could also be dangerous.

Neither Clone1 nor S-151128 changed the paw withdrawal threshold in healthy rats. Further assessments revealed treatment with Clone1 had no effect on the rat’s movement. These important findings suggest that the antibodies could reduce the abnormal pain responses associated with nerve injury without producing detectable effects on normal mechanical sensitivity.

To confirm the mechanism of action of the antibodies’ pain reducing behaviour, the researchers measured the levels of phosphorylated-extracellular-signal-regulated kinase (p(ERK)). Increased production of p(ERK) is associated with neuropathic pain. In the rats with a damaged sciatic nerve, mechanical stimulation increased the levels of p(ERK), whereas treatment with Clone1 reduced this response.

Together, these findings provide sufficient evidence that therapeutic antibodies could reduce pain-related activity within the nervous system, rather than simply changing the animal’s behaviour.

A novel therapy with the potential to transform neuropathic pain management

This paper presents some impressive preclinical evidence that antibodies designed to target Nav1.7 could be used as effective, long-lasting treatments for neuropathic pain.

However, neuropathic pain exists in many forms and this study only examined one of them. Further experiments will be needed to assess the variety of neuropathic pain that antibody therapies could treat.

Nevertheless, this research is making advancements towards clinical development. Antibody S-151128 is currently in clinical trials. Successful results from these trials would demonstrate that the promising findings observed in animal models could translate into a treatment for people with neuropathic pain.

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