Rare Hereditary Pain Insensitivity Syndrome Yields Insight into Treating Chronic Pain

A mouse study finds that blocking a protein called WNK1 can improve pain from nerve injury. Image credit: lonely11/123RF Stock Photo.

Sometimes rare genetic diseases can help scientists learn about more common conditions. Now, a new study in mice reports that a protein altered in a rare hereditary form of pain insensitivity contributes to chronic pain, and is a potential new target for development of new pain-relieving drugs.

The research, led by Kristopher Kahle, now at Yale School of Medicine, New Haven, US, and Guy Rouleau, McGill University, Montreal, Canada, was published March 29 in the journal Science Signaling.

Learning from those who can’t feel pain
In 2009, Rouleau and colleagues discovered that mutations in a portion of the gene that makes a protein called WNK1  lead to hereditary sensory and autonomic neuropathy type IIA (HSANII), an inherited form of pain insensitivity present at birth (WNK1 is a type of protein called an enzyme that belongs to a class of enzymes known as kinases). However, how the mutations produced the pain insensitivity was unknown.

To explore further, the researchers developed a mouse model of HSANII by removing—“knocking out”—the same portion of the WNK1 gene that is mutated in the human disease. This means that the knockout animals would also lack the WNK1 protein.

Overall, the knockout mice behaved largely normal on tests of pain sensitivity and general behavioral and neurological function. “Knocking out the whole gene didn’t have a very big effect,” Kahle explains. “However, digging a little deeper, we wondered if maybe the [WNK1 protein] is protective or exacerbative in conditions under which we know this [molecular] pathway [involving WNK1] might be important, such as neuropathic pain,” he added, referring to the pain that results from nerve injury.

To answer that question, the researchers examined the effect of knocking out the gene in two models of chronic pain. In the spared nerve injury model of neuropathic pain, in which portions of the sciatic nerve are severed, animals become more sensitive to mechanical stimuli, in this case a poke to the paw with a filament, and to cold stimuli, such as a chemical applied to the foot pad of the animals. In a model of inflammatory pain, where an inflammatory substance is injected into a hind paw, the mice become more sensitive to mechanical stimuli, and to heat stimuli such as a high-energy beam of light.

Compared to mice that still had the gene (so-called “wild-type” animals), WNK1 knockout mice exposed to spared nerve injury showed significantly reduced levels of pain in response to the poke and to cold. In contrast, both wild-type and WNK1 knockouts showed similar levels of mechanical and heat pain in the inflammatory pain model. Together, the results suggest that WNK1 knockouts show reduced pain hypersensitivity following nerve injury, but not following inflammation.

“Taken in the context of the finding that complete knockout of the protein [the WNK1 kinase] didn’t have any bad systemic [i.e., throughout the body] effects, our results are exciting and suggest that inhibition of the WNK1 kinase with a drug would not only produce no side effects, but would selectively impact neuropathic pain behaviors without toxicity,” Kahle says.

Diminished pain, but why?
In additional experiments, the researchers turned to why the knockout mice had less pain than normal animals. They focused on a protein called KCC2, which regulates the concentration of ions (electrically-charged molecules) in neurons (nerve cells); this helps to control neuron-to-neuron communication.

“Numerous groups have shown before that KCC2’s function is inhibited or completely reduced in neuropathic pain, but no one really knew why,” Kahle explains.

In the new study, the researchers found that when WNK1 made a chemical modification to KCC2—in this case, by adding phosphate molecules to KCC2 (a process termed phosphorylation)—it blocked the activity of KCC2. Ultimately this results in greater levels of communication between nerve cells. The net result is an increase in the transmission of pain signals to the brain.

In mice that had received spared nerve injury, the removal of WNK1 in the knockout mice, or use of a drug to inhibit the activity of WNK1, blocked the phosphorylation and restored nerve cell signaling levels. These effects could explain why the knockout animals were less susceptible to pain from the nerve injury.

The current study provides motivation for taking a closer look at how inhibiting WNK1 could treat neuropathic pain, and the team is currently working on developing new WNK1 inhibitors, Kahle says.

Interestingly, loss of KCC2 function has been associated with several neurological disorders besides chronic pain, including epilepsy, motor spasticity, stress disorders, and possibly schizophrenia. “It will be intriguing to know if targeting KCC2 may also [prove to be a] therapeutic avenue for these other disorders,” says Yves De Koninck, Laval University, Quebec City, Canada, who not involved in the new study. —Allison Marin

To read about the research in more detail, see the related Pain Research Forum news story here.

Allison Marin, PhD, is a neuroscientist-turned-science writer who resides in Pittsburgh, Pennsylvania, US.