A new study has found an old antipsychotic drug blocks a signaling pathway that has been linked to chronic neuropathic pain. The surprising findings not only point to novel future treatments for pain but reveal an unexpected association between chronic pain and lung cancer.
“Chronic pain is currently subjected to often ineffective palliative treatments,” said co-corresponding author Clifford Woolf, explaining the origins of the research. “Furthermore, effective painkillers such as opioids can lead, if used inappropriately, to severe addiction. It is therefore critical to find and develop new and repurposed drugs to treat chronic pain.”
Prior investigations from the researchers led to the discovery of a particular signaling pathway unique to chronic pain. They found a metabolite called BH4 is produced by sensory neurons in cases of neuropathic and inflammatory pain.
High levels of BH4 had been linked to severe pain intensity in chronic pain cases, so the next step was to look for drugs that could block BH4 signaling in pain neurons.
To do this, the researchers performed a phenotypic screen on around 1,000 known bioactive molecules. They were looking for drugs that could regulate the expression of the gene linked to higher levels of BH4.
Several currently used medicines popped up in the screening study, including drugs like clonadine that are known to generate analgesic effects. But most interesting was the discovery that an old anti-psychotic drug called fluphenazine seemed to work on this particular pain-signaling pathway.
“… our phenotypic screen also allowed us to ‘repurpose’ a surprising drug,” said project lead Shane Cronin. “We found that fluphenazine blocks the BH4 pathway in injured nerves.”
Testing fluphenazine in mouse models the researchers discovered low doses of the drug did indeed suppress pain from nerve injury. It’s unlikely fluphenazine will be directly repurposed as a pain-relieving drug but instead the findings affirm that targeting this BH4 could be a good way to treat chronic pain.
The most unexpected finding in the new study was a link between BH4 and lung cancer. Looking at mouse models of lung cancer, the researchers discovered decreasing levels of BH4 also slowed tumor growth. Co-corresponding author Josef Penninger said this compelling mechanistic link between chronic pain and certain types of cancer should help inform future research into therapeutics for both conditions.
“The same triggers that drive tumor growth appear to be also involved in setting the path to chronic pain, often experienced by cancer patients,” said Penninger. “We also know that sensory nerves can drive cancer, which could explain the vicious circuit of cancer and pain.”
The new study was published in Science Translational Medicine.
Source: Institute of Molecular Biotechnology of the Austrian Academy of Sciences
