Media release

From: CSIRO

Nerve pain, also known as neuropathic pain, is usually chronic and can be experienced for a range of reasons such as cancer, diabetes, trauma, infection, and multiple sclerosis. It is estimated to affect 1 in 20 Australians. 

Symptoms vary from shooting or throbbing pain, burning, freezing or electrical shock sensations, tingling, itchiness, oversensitivity or numbness. 

Although TCAs are listed as a drug treatment of choice for neuropathic pain in the Australian Medical Handbook, how they work to limit pain has not been fully understood, until now.  

Recently published in RSC Medicinal Chemistry, a multi-disciplinary team of researchers from CSIRO, The University of Queensland’s Institute for Molecular Bioscience and Monash University used a neuroblastoma cell line to demonstrate exactly how 11 TCAs and 2 closely related drugs worked to block pain, and identified which ones were most effective.  

“Using both biological assays and computer simulation, we showed all test drugs moderately inhibited N-type calcium ion channels - tiny gates that are instrumental in the transmission of pain signals in the body. Though suspected, this is the first time such a broad set of TCAs have been proven to block these channels,” CSIRO scientist and lead author, Adjunct Professor Peter Duggan said.  

“Seven of the drugs we investigated showed more than a two-fold stronger inhibition than the channel blocker we used as a control, and with the assistance of computer modelling we were able to predict exactly where and how all 13 drugs interacted with these ion channels. 

“We are now looking to better understand how TCAs affect the different states of the ion channels (resting, open, closed) as the nerve impulses go from the extremities to the brain. 

“Knowing how pain impulses are inhibited by TCAs is expected to lead to new and improved treatment options for people suffering neuropathic pain – and the more we work in this space the more our science opens up the possibility of effective pain therapies, free of any potential side-effects.” Professor Duggan said. 

Dean of the Faculty of Pain Medicine at the Australian and New Zealand College of Anaesthetists and Clinical Associate Professor at Deakin University, Michael Vagg sees the human cost of chronic pain as well as the broader social and economic impact it has for our community.  

“Nerve pain is highly disabling and ruins lives. The best current treatments only work to a useful degree on every third or fourth person who receives them,” A/Professor Vagg said. 

“Tricyclic drugs have been used for decades in treating nerve and musculoskeletal pain and are still the most likely drugs to help despite all the effort that has been put into researching new treatments. 

“TCAs have a number of pharmacological effects throughout the body and this work is fascinating in that it suggests that one specific mechanism is critically important to their effect on nerve pain. 

“We have not had any really effective new treatments for nerve pain for a long time and this work opens up the possibility of designing a new class of drugs with improved safety and effectiveness,” he said.  

With further work already underway, the team is aiming to provide the scientific basis that leads to the design of more effective drugs to improve the lives of people living with nerve pain. 

CSIRO is helping Australia’s biomedical industry grow locally and compete globally through innovative science and technology. CSIRO’s commercially-minded approach to research and development attracts local industry ready to partner and progress ideas into biomedical innovations.   

Additional notes

Compounds tested: 

Imipramine (1), desipramine (2), amitriptyline (3), clomipramine (4), nortriptyline (5), trimipramine (6), doxepin (7), protriptyline (8), opipramol (9), maprotiline (10), amoxapine (11), and two structurally-related drugs, the muscle relaxant cyclobenzaprine (12) and the sedating antihistamine promethazine (13).  

It was found that all of the above drugs showed moderate inhibition of the calcium channel, with 2–6, 8, 10 and 12 eliciting slightly stronger responses.