Researchers assessing the role that venom plays in activating nerve fibers involved in pain sensation have uncovered a surprising mechanism that may influence irritable bowel syndrome (IBS)-related pain.
An estimated 10 to 15 percent of Americans live with IBS, according to the American College of Gastroenterology. A diagnosis of exclusion, the syndrome can cause lower abdominal pain, bloating and changes in bowel habits. While some patients have mild symptoms that respond to over-the-counter medication, others experience significant pain and distress that greatly affect their quality of life. Brian Kirsh, MD, a gastroenterologist at Cleveland Clinic, has evaluated patients who have rated their IBS-associated pain as high as 10 on the Comparative Pain Scale.
There is currently no cure for IBS, but management strategies can relieve symptoms. First-line therapies include antispasmodic medications designed to prevent abdominal-muscle contractions. In the past five to 10 years, the FDA has also approved medications for constipation-predominant and diarrhea-predominant IBS. Additionally, some patients benefit from behavioral and dietary modifications, as well as complementary therapies, such as hypnosis and relaxation therapy.
Despite the availability of medication and other management strategies, many people — especially those who have post-infectious IBS or mixed-motility IBS, which presents as alternating episodes of constipation and diarrhea — continue to experience chronic abdominal pain.
An Unexpected Discovery
The international team behind research published recently in Nature did not initially intend to study IBS. Rather, the researchers sought to gain further knowledge about the activity of sensory nerve fibers that are devoted to painful stimuli. Of particular interest to the team were naturally occurring, pungent agents that are known to activate nerve fibers involved in pain sensation. David Julius, PhD, a co-lead author of the study and Professor and Chair, Department of Physiology, University of California, San Francisco, has previously focused on the role of capsaicin and wasabi in stimulating a pain response. Studying venom was a natural evolution.
“An underlying cause of the chronic abdominal pain suffered by IBS patients is the abnormal increase in pain signals being sent from the gastrointestinal tract to the brain. In particular, low-threshold mechanical events within the gastrointestinal tract are often perceived as painful by IBS patients. We have discovered that Nav1.1 plays a key role in this pathological pain signal. Therefore, inhibiting this channel on nociceptors that innervate the gastrointestinal tract is a key step in blocking mechanical pain at its source.”
— Professor Stuart Brierley, PhD, Head of the Visceral Pain Research Group at Flinders University and the South Australian Health and Medical Research Institute
“The study [was] based on the premise that creatures such as spiders have evolved over millions of years to be very successful in surviving within their environment,” says Professor Stuart Brierley, PhD, a co-lead author of the study and Head of the Visceral Pain Research Group at Flinders University and the South Australian Health and Medical Research Institute in Adelaide. “Therefore, the venom they release when they bite is not just used to capture prey for food — it also needs to be used to deter predators. The best way to deter predators is to inject them with something that causes immediate pain. Thus, we screened a large panel of spider and scorpion venoms, looking for those that activated pain-sensing neurons.”
Researchers screened 109 spider, scorpion and centipede venoms using a cell-based assay. Once a “hit” venom — one that elicited strong activation of pain-sensing neurons — was identified, the venom was fractionated into individual peptide components to identify the active molecule responsible for inducing pain. Venom from the tarantula species Heteroscodra maculata elicited the most robust response. Toxins found in the venom induced the pain response by acting on the Nav1.1 voltage-gated sodium channel.
“Once we identified Nav1.1, this was interesting to us because we know that sodium channels are important, as they are in all neurons for sending signals from the periphery to the central nervous system and spinal cord,” Julius says. “But in all of the sodium channels that had been looked at, Nav1.1 hadn’t received much attention. The fact that these spiders have evolved toxins to interact with this channel piqued our interest and made us think that this channel was playing a more important role in pain sensation than people previously thought.”
Taking their investigation one step further, researchers injected the Hm1a toxin into the hindquarters of mice to determine what type of pain response was elicited. The Hm1a toxins activated nerve fibers that generate signals associated with a type of pain endemic to IBS sufferers.
“Our study shows that Nav1.1 plays a critical role in transmitting information about mechanical pain to the brain,” says Professor Glenn King, a co-lead author of the study and National Health and Medical Research Council Principal Research Fellow at the Institute for Molecular Bioscience in Brisbane, Australia. “Mechanical pain is the pain experienced, for example, if you accidentally hit your finger with a hammer, and it is also the type of gut pain experienced by people with IBS.”
Using a preclinical mouse model of IBS, in which gut-nerve preparations from healthy mice and mice with chronic visceral hypersensitivity were exposed to Hm1a toxins, researchers were able to confirm that Nav1.1 activation does play an important role in transmitting pain signals from the gut to the central nervous system.
Path to Treatment
Examining whether or not Nav1.1’s activity is enhanced in the presence of an injury, such as gut inflammation, may be the focus of additional investigation. In a follow-up collaborative effort, King and Brierley have also developed Nav1.1 inhibitors that may form the basis for future pharmacologic agents.
“We have one lead molecule already [a spider-venom peptide] that is proving highly efficacious in reducing mechanical pain in a mouse model of IBS,” King says. “We hope to publish a paper on this work very soon.”