By tweaking the chemical structure of oxytocin — the love and bonding hormone — researchers created a new oral drug that relieves abdominal pain in a mouse model. It could be a promising therapeutic option for managing chronic pain in people with irritable bowel syndrome and gastrointestinal disorders such as Crohn’s disease.
“Abdominal pain is one of the most insidious types of chronic pain,” said David Andreu, a medicinal peptide chemist at Pompeu Fabra University. “The conventional approaches to pain management have problems, each one of them,” he added. The recommended treatments include nonsteroidal anti-inflammatory drugs, which can exacerbate symptoms, and opiates with high abuse potential.
In a recent study published in Angewandte Chemie International Edition, senior author Markus Muttenthaler and his colleagues described this novel oxytocin-derived painkiller (1).
“Our approach is to identify receptors that work in the gut, in the colon, or its afferent neurons, and suppress the pain within the gastrointestinal system,” said Muttenthaler, who is a medicinal chemist at the University of Vienna and the University of Queensland.
Abdominal pain is one of the most insidious types of chronic pain.
- David Andreu, Pompeu Fabra University
In a 2014 study, Muttenthaler and his colleagues discovered that there were higher numbers of oxytocin receptors in colonic neurons in mice with chronic abdominal pain than in healthy mice (2). The cells on which the receptor was present, afferent neurons, transmit sensory information from the gut to the brain, triggering responses such as vomiting and diarrhea. Activating the oxytocin receptor interfered with pain signaling, which tipped the team off to its analgesic potential.
However, digestive enzymes degrade natural oxytocin within 10 minutes, so if Muttenthaler and his colleagues wanted to make an oral drug for abdominal pain, they first had to make oxytocin gut stable.
To do so, they identified the molecule’s weak points — where it breaks during digestion — and fortified those sites with more robust chemical groups. This painstaking effort took more than two years and resulted in around 60 oxytocin-like variants, several of which resisted degradation and continued to activate the right receptor.
The team then tested one of these drug candidate molecules in a mouse model of chronic abdominal pain by inserting a small balloon into the abdominal cavity and monitoring pain levels as the pressure increased. Mice that took the drug displayed a reduced pain response, as evidenced by neuronal activity, compared to those that received no treatment, suggesting that the medication was working.
“They’ve done a very good job in terms of peptide chemistry,” said Andreu. “The structure-activity work is impeccable.”
The team filed an international patent, but the drug won’t be available for patients anytime soon. They will need to rule out off-target effects, toxicity responses, and aberrant immune activity, Andreu noted. Muttenthaler agreed that the road ahead is long and said they are optimistic about the drug’s potential. The team is also eager to try developing other new drugs in this same way.
“So far, everyone’s ignored peptides in the gut space,” said Muttenthaler. Most protein-based drugs on the market, such as insulin and the GLP-1 agonists, are injectable. The oral route constrains the drug to the gastrointestinal tract, which differs from other painkillers — like opiates — that treat pain by numbing everything.
“Our approach, where we look at targets within the gut, that’s completely unexplored.”
References
- Kremsmayr, T. et al. Oxytocin Analogues for the Oral Treatment of Abdominal Pain. Angewandte Chemie International Edition 63, e202415333 (2024).
- de Araujo, A. D. et al. Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain. Nat Commun 5, 3165 (2014).
