A segment of the sodium channel Nav1.7, which is defective in people who display complete insensitivity to pain. However, attempts to recreate the condition with Nav1.7 antagonists were unsuccessful, and require the addition of opioids. (Source: Wikimedia Commons, Credit: Jawahar Swaminathan and the European Bioinformatics Institute)
Pain serves an important function in alerting the body to negative inputs and preventing damage. However, some people with a mutation in the SCN9A gene, which codes for the critical sodium channel Nav1.7, are unable to sense any pain at all (1). Pain insensitivity is an extremely rare condition, with only about 20 reported cases throughout history. In the past, these subjects often died at a young age due to severe injuries that went unnoticed.
Until recently, studies attempting to recreate the condition using Nav1.7 channel blockers have only produced mild analgesia, or partial insensitivity to pain. Now, researchers at the University of College London (UCL) have presented a new model involving the role of endogenous opioids in activating Nav1.7 in pain’s neural pathway (2).
Most people sense pain when high intensity mechanical or mechanothermal stimuli cause ion channels, such as Nav1.7, to open. This initiates an action potential in a nociceptor, or pain-sensitive neuron, and sends a cascade of pain signals to the brain via the spinal cord (3). People with congenital insensitivity to pain (CIP) lack the sodium channel Nav1.7. As a result, nociceptors cannot transmit information about painful stimuli to the brain, and these people experience complete analgesia. Interestingly, sodium channel Nav1.7 is also found in large quantities in the olfactory system, and many people who cannot feel pain also lack a sense of smell, a condition known as anosmia (2). However, antagonists of Nav1.7, which block the channel from sending any signals, do not reproduce the effect of anosmia (1).
The team at UCL used transgenic Nav1.7 knockout mice models, which display complete analgesia, to study CIP. The team observed that mice lacking Nav1.7 generated higher concentrations of proenkephalins, or precursor mRNA, when treated with endogenous opioids. This suggests that opioids work in conjunction with Nav1.7 antagonists to produce complete analgesia, which would explain why simply blocking Nav1.7 channels did not produce CIP.
To test their hypothesis, researchers administered naloxone, an opioid blocker, to the Nav1.7 knockout mice and found that the transgenic mice responded to painful stimuli. Additional trials in a 39-year-old woman with CIP also supported the new model of opioid and ion channel interaction, as she felt pain for the first time after receiving a low dose of naloxone.
These findings are not only useful for those afflicted with pain insensitivity; they also present significant implications for the treatment of chronic pain. Affecting approximately seven percent of the population, chronic pain is often treated with opioid painkillers alone (2). Though effective, prolonged use and high doses of painkillers often lead to addiction. When used with Nav1.7 blockers, opioid doses can be decreased significantly. Researchers hope to develop new, combined analgesics by 2017 (1).
References:
- University College London. (2015, December 4). Genetically modified mice reveal the secret to a painless life: Researchers have discovered the pharmaceutical recipe for painlessness. ScienceDaily. Retrieved from www.sciencedaily.com/releases/2015/12/151204090034.htm
- Minett, M. S., Pereira, V., Sikandar, S., Matsuyama, A., Lolignier, S., Kanellopoulos, A. H., . . . Wood, J. (2015). Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7. Nature Communications, 6, 8967-8967. doi:10.1038/ncomms9967
- Purves, D., Augustine, G., & Fitzpatrick, D. (2001). Nociceptors. In Neuroscience (2nd ed.). Stamford, CT: Sinauer Associates.