Scientists have discovered that the body can naturally dull pain through its own localized “benzodiazepine-like” peptides.

A groundbreaking study led by a University of Leeds scientist has unveiled new insights into how the body manages pain, offering a potential path toward treating long-term pain without relying on addictive opioids.

Professor Nikita Gamper, from the School of Biomedical Sciences at Leeds, and his research team discovered that the human body can generate its own form of natural “sleeping pills” that resemble benzodiazepines. These substances can reduce signals from specific nerves, influencing how intensely pain is felt.

The research, which builds upon earlier studies conducted by Professor Gamper and Professor Xiaona Du of Hebei Medical University in Shijiazhuang, China, could mark a turning point in pain management. With new funding secured for the coming year, the team plans to continue exploring how this biological process could lead to safer, more effective treatments for people suffering from chronic pain.

A New Path Beyond Opioids

Professor Gamper said: “We understand quite a bit about how a person ends up feeling pain, but we can’t do much about it. Despite all the amazing discoveries and textbooks written, opioids are still the gold standard.

“Nothing substantially better than opioids has been produced. If you suffer from pain, you will likely end up with either ibuprofen, which is OK for mild pain, but absolutely does nothing for very strong pain or neuropathic pain; or opioids which are very efficacious but dangerous.”

Benzodiazepines (‘benzos’) are a type of depressant medication commonly prescribed to help with sleep problems, anxiety, and seizures. In their research, Professor Nikita Gamper, Professor Xiaona Du, and Dr. Temugin Berta from the University of Cincinnati discovered that certain cells connected to human nerves, located within structures known as spinal ganglia, can release a peptide that operates in a similar way to benzos.

Because this process takes place only within the peripheral nervous system, it does not cause the entire nervous system to “go to sleep.” As a result, these naturally produced peptides could offer pain relief without the dangerous side effects or risk of addiction associated with opioid drugs.

The study’s results show that nerves are capable of “tuning out” pain signals or limiting how much pain the brain perceives, revealing a potential new mechanism for controlling discomfort at its source.

Turning Down Pain at Its Source

Dr. Ganesan Baranidharan, a consultant in pain medicine in Leeds, said the findings could offer some hope to patients trying to manage daily chronic pain.

He said: “Chronic pain is one of the health service’s biggest problems.

“In clinics we try to manage pain with ‘self management’ – learning to live with pain – or we try to help where we can with physiotherapy, injections, or surgeries. However, some patients will have persistent pain needing medicines, and long-term use of nerve painkillers and opioids can cause significant side effects such as feeling like a zombie, memory impairment, etc.

“While some patients do really well on small dose opioids, we need more options to treat chronic pain. The more we can discover, and find appropriate drugs to treat certain conditions, the better for our patients.”

Toward Safer Pain Treatments

Professor Nikita’s findings – published in the Journal of Clinical Investigation (JCI) – open up the possibility of developing new, targeted medicines that could block pain signals without crossing the blood-brain barrier and affecting other brain functions.

For up to a third of the world’s population, pain is a daily burden, and despite being the primary reason for doctor visits across the world, pain is still poorly treated.

Cincinnati’s Dr. Berta, whose research is sponsored by the NIH HEAL initiative, added: “Millions of people suffer from chronic pain and more than half have trouble finding adequate relief. As pain scientists, we have the opportunity to discover new mechanisms that contribute to the progression of chronic pain and share breakthroughs that may hold promise for new treatment strategies.”

Professor Gamper’s decision to focus his work in this area was strongly influenced by seeing a member of his immediate family suffer with neuropathic pain.

He added: “Pain is an interesting phenomenon to study, but ultimately it’s not curiosity that drives you, it’s the ability or at least opportunity to relieve people from pain.”

The teams in Leeds and Shijiazhuang worked together from the research’s inception, with Dr. Berta in Cincinnati coming on board after the scientists discussed their work at a Society for Neuroscience conference in 2018.

Although the scientists had not previously met, they knew each other’s wor,k and by sharing knowledge, they soon realized they had been working on similar experiments and produced identical results. Dr. Berta believes their work “embodies the collaborative spirit of academic research” and shows how significant advancements in understanding and treating pain can be made when scientists work together.

Professor Du said: “I vividly recall the excitement when Nikita informed me that Temo’s lab had obtained similar primary results to ours, solidifying our decision to pursue the study further.

“I hope that our future collaboration will yield even more and better outcomes.”

New Research Funding

A research team led by Professor Gamper in Leeds has now received £3.5 million in funding from the Medical Research Council and the pharmaceutical industry to look further into their findings. A new project was started in January 2025 and will run for five years, looking more closely at potential markers of neuropathic pain and new approaches for pain management, incorporating this new knowledge about spinal ganglia and the ‘benzo’ peptide.

Reference: “Peripheral gating of mechanosensation by glial diazepam binding inhibitor” by Xinmeng Li, Arthur Silveira Prudente, Vincenzo Prato, Xianchuan Guo, Han Hao, Frederick Jones, Sofia Figoli, Pierce Mullen, Yujin Wang, Raquel Tonello, Sang Hoon Lee, Shihab Shah, Benito Maffei, Temugin Berta, Xiaona Du and Nikita Gamper, 18 June 2024, The Journal of Clinical Investigation.
DOI: 10.1172/JCI176227

Funding: Wellcome Trust, Medical Research Council, Biotechnology and Biological Sciences Research Council, Biotechnology and Biological Sciences Research Council, Horizon 2020 Framework Programme, National Natural Science Foundation of China, Science Fund for Creative Research Groups, NIH/National Institute of Neurological Disorders and Stroke

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