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Humans who can’t feel pain pointing way to non-addictive painkillers

| August 3, 2016

Mannish and Dinkal Patel, ages 7 and 5, feel no pain. The Indian siblings are so blind to physical discomfort that they reportedly chewed off the ends of their own fingers. Their family has at least one congenital mutation in the SCN9A gene—which codes for a protein that is vital for a cell’s ability to generate and transmit electrical signals through the nervous system.

That gene is being eyed as potential target for developing new, non-addictive pain killers.

Scientists discovered SCN9A by investigating the genetics of families that include pain-insensitive people like the Patels and other families in which some members are super-sensitive to pain. The latter often feel a horrible burning on their skin brought on by minor amounts of heat, exercise or even alcohol. These families also have mutations in their SCN9A gene. But these mutations increase the number of pain-related sodium channels in nerves and neurons instead of inactivating them like the Patel mutation.

Pain is a signal of self-protection that the body sends to the brain. When something hurts, one usually tries to avoid it. And for good reason says Mo Costandi writing at the Guardian.

Pain is, for most of us, a very unpleasant feeling, but it serves the important evolutionary purpose of alerting us to potentially life-threatening injuries. Without it, people are more prone to hurting themselves and so, because they can be completely oblivious to serious injuries, a life without pain is often cut short.

These dramatic examples led scientists to find variants of the gene that may relate to more common forms of chronic pain. Some variants of the SCN9A gene have been linked to the development of diabetic nerve pain. People with these variants were twice as likely to develop the condition. One Chinese group genotyped women undergoing gynecological surgeries to see if their gene status would predict how much pain they felt after surgery. They found a connection, but the study was small.

SCN9A contains instructions for making the Nav1.7 protein that forms part of a sodium channel, a pore that allows sodium molecules in an out of cells. Those molecules essentially carry with them an electrical signal that runs through the nerve. If these pores are malformed, like in some SCN9A mutations, the nerve signal doesn’t get relayed up the sensory nerves and into the brain. Other SCN9A mutations cause faulty sodium channels in the neurons at the base of the brain that pick up on pain signals sent from the body.

Drug companies think that SC9A and the Nav 1.7 protein are good places to start looking for new painkillers. A pill that blocks or disables the Nav 1.7 protein could keep the body from sensing pain. But the drug wouldn’t affect the entire neurological system because Nav1.7 only affects pain and pain perception in the extremities. And, it might not be addictive, explains Ricki Lewis on PLOS blogs:

The channels are not on neurons in the heart or of the central nervous system, and the children in whom the channels don’t work do not have any symptoms other than their painlessness. The possibility of adverse effects seems low.

Opiates, by contrast, act globally across the central nervous system and are extremely addictive and sometimes deadly. Unfortunately they are also the primary option for treating pain. Damian Garde at STAT:

Opioid prescriptions have more than quadrupled since 2009, according to the Centers for Disease Control and Prevention. Opioid abuse kills about 30,000 Americans each year, according to the agency, and about half of those deaths result from prescribed therapies.

Companies are already working on drugs to target Nav1.7 pain pathway. In January 2015, Biogen, a large biotech company, bought a small UK firm that developed a potential molecule. And Pfizer conducted two trials of a pill, one in dental pain and one for diabetic neuropathy, but neither was very successful according to Garde.

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Other pain genes have potential, too. PRDM12, for example, appears to stop pain fiber growth all together, writes Costandi at the Guardian:

The PRDM12 mutations cause pain insensitivity another way. When Woods and his colleagues examined biopsies from several of the affected people they studied, they found that the skin in their legs contains no nerve endings whatsoever, and that one of the sensory nerves in their legs contains about half the normal number of pain-sensing fibres. This led them to speculate that PRDM12 plays an important role in the development of pain-sensing neurons and their fibres.

It’s possible that someday one of these pathways will lead to the development of a new class of painkillers, one that can block pain more specifically and more safely than opiates do. But with the slow pace of drug development and safety testing, these pain blockers probably won’t be widely available to patients for at least a few years.

Meredith Knight is a contributor to the human genetics section for Genetic Literacy Project and a freelance science and health writer in Austin, Texas. Follow her @meremereknight.

The GLP featured this article to reflect the diversity of news, opinion and analysis. The viewpoint is the author’s own. The GLP’s goal is to stimulate constructive discourse on challenging science issues.

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