An antibody to the paddle-shaped voltage sensor of the Nav1.7 sodium channel calms pain and itch in mice, according to a study published May 22 in Cell. The study, a collaboration between Seok-Yong Lee and Ru-Rong Ji, both at Duke University, Durham, North Carolina, US, shows that the antibody selectively suppresses currents flowing through Nav1.7, a sodium channel linked to pain. The antibody also reduces pain and itch responses in mouse models of inflammatory pain, neuropathic pain, and acute or chronic itch.
The findings point to a role for Nav1.7 in both pain and itch sensations, and suggest that antibodies offer a feasible way to inhibit the channel therapeutically.
“It’s pretty exciting because it’s really the first clear indication that antibodies can be used to target ion channels in an important disease state,” said Ted Cummins, a researcher at Indiana University, Indianapolis, US, who was not involved in the study.
Cummins originally discovered that the region recognized by the new antibody is the target of a channel-inhibiting tarantula toxin (Xiao et al., 2008). Although several peptide toxins bind the same region in other sodium channels, the new antibody binds Nav1.7 more selectively than any of them, he added.
Nav1.7 has been an enticing target for new analgesics since mutations in the gene encoding the channel (SCN9A) were found in people with congenital pain insensitivity and inherited pain syndromes. Found in the axons of small, pain-sensing dorsal root ganglion (DRG) cells, Nav1.7 channels play an important role in generating action potentials that convey pain signals from the periphery to the spinal cord.
But selectively blocking Nav1.7 channels is complicated because they resemble the other eight voltage-gated sodium channels, all of which have important physiological functions. Non-selective sodium channel blockers can cause numbness, paralysis, or even death.
The new study went after a small distinguishing feature in Nav1.7: a short loop at the tip of the mobile voltage-sensor paddle, which acts as an on/off switch for the channel. Developing an antibody to prevent the movement of the paddle seemed like a good bet because, unlike small molecules, antibodies can recognize subtle differences in protein shape.
“If you can grab this region with an antibody selectively, then you can actually modulate the channel’s function,” Lee told PRF. Trained as a biophysicist, Lee raised antibodies to help crystallize proteins for structural studies. Upon starting his own lab, he realized this skill might be useful for making antibodies as therapeutics.
After one and a half years of work, Lee had a mouse monoclonal antibody that selectively suppressed Nav1.7 currents. He enlisted the help of Ji, a pain and itch researcher, to test the antibody in mice. It quelled pain and itch responses, without introducing deficits in motor or somatosensory processes.
“We are very excited, but there’s a lot of work to do before it can be a drug in humans,” Ji said.
The antibody strategy may be fruitful for developing selective inhibitors for other channels, too. Subtypes of voltage-gated calcium or potassium channels differ from each other in the voltage-sensor region.
Paddling away from pain, itch
First author Jun-Ho Lee and colleagues first characterized the antibody in cultured cells expressing Nav1.7 channels and found that it suppressed the inward sodium currents activated by depolarization. In contrast, the antibody did not touch currents through other sodium channel subtypes, except for a small effect on Nav1.6. This amounted to selectivity for Nav1.7 that was 400-1,500 times greater than that for other sodium channel subtypes—the highest ever reported for any Nav1.7 inhibitor.
In mice, the antibody reduced pain responses to formalin injections to the paw. Whether delivered intrathecally into the spinal cord or systemically under the skin, the antibody shortened the duration of licking and flinching that follows formalin injection, particularly during the later, inflammation-related phase. Mice were not simply numbed up, however, as they could still muster normal coordination to balance on a rotating rod.
The antibody also provided pain relief in a model of neuropathic pain in which chronic constriction of the sciatic nerve brings about hypersensitivity to touch in the paw. With the antibody on board, mice could withstand more intense stimulation than mice with a control antibody did. This effect lasted hours after antibody injection and could be revived with additional injections with no sign of tolerance.
The antibody also calmed acute itch brought on by histamine-dependent and histamine-independent agents, as well as chronic itchiness from dry skin. In all paradigms, the antibody halved the number of scratches observed in treated animals.
Experiments in isolated DRG neurons and spinal cord slices suggest that the antibody has a dual-pronged effect, both at the periphery where pain signals are initiated and in the spinal cord, where pain messages are passed along. The results implicated Nav1.7 channels for the first time in modulating glutamate release from DRG neurons at synapses in the spinal cord.
“These two sites of action may be key to the antibody’s success,” Ji said.
Michele Solis is a science writer and former neuroscientist who lives in Seattle, Washington, US.
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