They study how “old” drugs can be used to fight pain

A new study suggests it might new treatments for chronic pain using drugs indicated for other diseases and with a surprising link to lung cancer, according to researchers published in the journal Science Translational Medicine.

The work, carried out in laboratory mouse models, was led by an international team of researchers from Institute for Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) and Harvard Medical School and Boston Children’s Hospital in the United States. Their results reveal a host of therapeutic options that could allow the world to improve chronic pain treatment and eclipse the opioid epidemic.

Acute pain is an important danger signal, while chronic pain is based on persistent injury and may even be experienced in the absence of stimulus, injury or disease. Despite the hundreds of millions of people affected, chronic pain is among the least managed areas of health care.

To improve treatment of persistent painand given the serious opioid crisis, it is essential to develop new drugs based on a fundamental understanding of the underlying mechanisms.

“We previously showed that sensory neurons produce a specific metabolite, BH4, that triggers chronic pain, such as neuropathic pain or inflammatory pain,” says project leader and co-author Shane Cronin, a scientist in IMBA’s Penninger Lab and a former postdoctoral fellow in the Woolf Lab at Harvard Medical School and the FM Kirby Neurobiology Center at Boston Children’s Hospital. BH4 concentrations correlate very well with pain intensity. So naturally we thought it was a great way to go.”

To identify drugs that reduce BH4 levels in pain neurons, researchers conducted a “phenotypic screeningo» of 1,000 drugs approved by the FDA. This approach allowed scientists to begin their search with drugs currently used for a variety of indications and to identify undescribed, off-target analgesic properties.

Between the first findingsBased on this hypothesis-driven search, the team was able to link the previously observed analgesic effects of several drugs, such as clonidine and capsaicin, to the BH4 pathway.

“However, our phenotypic screening also allowed us to “reuse” an amazing drug,” says Cronin. It’s fluphenazine, an antipsychotic drug that’s used to treat schizophrenia. “We found that fluphenazine blocks the BH4 pathway in damaged nerves. We also demonstrated its effects on chronic pain after nerve damage in vivo. “

researchers also found that the effective analgesic dose of fluphenazine in their mouse model experiments was comparable to the lower end of the safely indicated doses for schizophrenia in humans.

In addition, the study revealed a novel and unexpected molecular link between the BH4 pathway and EGFR/KRAS signaling, a pathway implicated in multiple cancers. Blocking EGFR/KRAS signaling reduces pain sensitivity by downregulating BH4 levels. The EGFR and KRAS genes are the two most commonly mutated genes in lung cancer, prompting researchers to investigate BH4 in lung cancer.

They found that, surprisingly, by suppressing an important enzyme, GCH1, in the BH4 pathway, lKRAS-driven mouse models of lung cancer they develop fewer tumors and survive much longer. Consequently, the researchers discovered a common signaling pathway for chronic pain and lung cancer via EGFR/KRAS and BH4, thus opening new avenues for treatment of both conditions.

“Nowadays, chronic pain is subjected to often ineffective palliative treatment. In addition, effective pain relievers such as opiates can lead to serious addiction if misused. Therefore, it is essential to find and develop new and repurposed drugs to treat chronic pain,” says co-author Clifford Wolff, professor of neurology and neurobiology at Harvard Medical School and director of the FM Kirby Center for Neurobiology at Boston Children’s Hospital.

An intriguing aspect of the study is the mechanistic link between pain and lung cancer. “The same triggers that stimulate tumor growth also appear to be involved in the onset of chronic pain, which is often experienced by cancer patients. We also know that sensory nerves can trigger cancer, which may explain the vicious cycle of cancer and pain.” co-author Josef Penninger, IMBA Group Leader and Founder, who is currently also Director of the Life Sciences Institute at the University of British Columbia (UBC), in Vancouver (Canada).

“So understanding these cross-links is not only critical for cancer treatment, but it can also help improve the quality of life of cancer patients towards less pain,” he concludes.

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