The African naked mole-rat does not look like the toughest critter. It comes clothed in pale, wrinkled, hairless skin and is nearly blind. Yet it thrives in extreme conditions, crowded into subterranean burrows where colonies of hundreds of animals produce levels of carbon dioxide that would be noxious to other rodents. Perhaps to cope with their unusual environment, naked mole-rats lack the painful response to acid and irritants that is seen in mice and rats, and in people.
Now, researchers have discovered one reason for the creature’s resistance to acid-induced pain: In naked mole-rats, the voltage-gated sodium channel Nav1.7, whose activity is largely responsible for the firing of pain-sensing neurons, is potently blocked by acid. The discovery, from Gary Lewin and colleagues at the Max-Delbrück Center for Molecular Medicine in Berlin, Germany, was reported in the December 16 issue of Science. The findings may suggest new ways to alter Nav1.7 function and diminish pain in humans.
Lewin, who has long studied sensation in mice, started investigating naked mole-rats through a collaboration with Thomas Park at the University of Illinois at Chicago. Park had noticed that C-fiber nociceptors in the animals’ skin lack Substance P and other pain-transmitting neuropeptides (Park et al., 2003). Lewin and Park also found that naked mole-rats are impervious to capsaicin-induced pain because, while their nociceptors express the capsaicin-sensitive channel TRPV1 and fire in response to the irritant, those neurons make unusual connections in the spinal cord that presumably prevent the signals from being processed as pain. When the stimulus is acid, however, the nociceptors do not even fire (Park et al., 2008).
In the new study, first author Ewan St. John Smith set out to find the basis for the acid insensitivity. He observed that proton-gated ion channels—TRPV1 and acid-sensing ion channels (ASICs)—were present in dorsal root ganglion (DRG) nociceptors from both mice and naked mole-rats, and the channels conducted current in response to acid just fine. Yet, in either species, the acid stimulus rarely led to an action potential.
Normally, when TRPV1 and ASIC channels open in response to a painful stimulus and cations trickle into the cell, the resulting increase in membrane potential activates voltage-gated sodium channels, which are responsible for the inrush of Na+ that creates an action potential. So the researchers looked at the sodium channels, and found they were inhibited by acidic pH. “Nobody had appreciated that protons were inhibiting action potential generation before,” Lewin said.
Importantly, acid blocked voltage-gated currents in neurons from both mice and naked mole-rats. But for naked mole-rats, the inhibition was stronger, apparently because of a species-specific substitution of two amino acids in a regulatory region of the Nav1.7 channel.
Lewin and his colleagues conclude that the response of nociceptors to acid represents a balance between two counteracting forces: Acid activates TRPV1 and ASIC channels, but it also blocks Nav1.7. In most species, the inhibition of Nav1.7 is slight, so the neurons fire in response to acid. But in naked mole-rats, the scales are tipped the other way, and acid squelches the action potential.
The ability to avoid pain from acidic conditions is likely crucial for naked mole-rats, whose high-carbon dioxide environment may make their tissues unusually acidic. People, too, often experience acid buildup in their tissues, but for them, it hurts. Protons produce acute pain and contribute to inflammatory pain.
Stephen Waxman, YaleUniversity, New Haven, and Veterans Affairs Medical Center, West Haven, Connecticut, said about the study, “The sodium channel Nav1.7 has been shown to be an important player in pain signaling. This study adds a new aspect to the channel’s action, by showing that exchange of two amino acids…makes the channel more sensitive to proton block than other sodium channels. The corollary, that inflammatory pain involves a balance between depolarizing inputs from TRPV1 and ASIC channels, and acid inhibition of sodium channels, is potentially important.”
Lewin predicted that nudging mammalian sodium channels to be a bit more proton-sensitive, as in the naked mole-rat, would make neurons send fewer painful signals. Nav1.7 antagonists are being avidly pursued to treat pain, but Lewin noted that altering the channel’s sensitivity to protons, rather than blocking its activation directly, would be a new approach. (For more on targeting Nav1.7 to treat pain, see related PRF news story.)
In other work that could open up new avenues to modulating sodium channel function therapeutically, researchers are making progress in understanding the structural basis for voltage gating. In July, a high-resolution crystal structure of a bacterial voltage-gated sodium channel was reported (see related PRF news story), and a computational model for the structural changes involved in voltage-dependent gating came out on December 12 (Yarov-Yarovoy et al., 2011, and see related video).
Besides the lack of cutaneous pain from acid and capsaicin, the naked mole-rat has other attributes of interest to pain researchers. It is tolerant to ammonia fumes (LaVinka et al., 2009), does not get itchy in response to histamine (Smith et al., 2010), and fails to develop hypersensitivity to heat in models of inflammatory pain (Park et al., 2008). Of more general interest, the rodent is a model of healthy aging: It lives for 30 years and resists cancer and other age-related diseases.
In pursuit of the underpinnings of the naked mole-rat’s hardy constitution, researchers recently sequenced its genome (Kim et al., 2011, and also see naked-mole-rat.org), a development that will enable efforts to lay bare more of this unusual rodent’s secrets to avoiding pain. At the moment, Lewin said, his group is working to track down the basis for the animal’s lack of inflammatory hypersensitivity to heat.
Image credit: Max-Delbrück Center for Molecular Medicine, Berlin, Germany.