Antipsychotic Drug Opens New Pathway To Beat Chronic Pain

Pain is a vital alarm system that warns us of tissue damage and compels us to leave potentially dangerous situations, despite the fact that it is uncomfortable. Although it is assumed that pain will lessen as wounds heal, many individuals continue to experience it even after they have recovered. Currently, a new study with an unexpected connection to lung cancer suggests potential new treatments for persistent pain. An international group of researchers from IMBA - Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Harvard Medical School, and Boston Children's Hospital led the project, which was reported in Science Translational Medicine. The research, which was carried out using laboratory mouse models, revealed several therapeutic possibilities that could help the globe better manage chronic pain and stop the opioid pandemic.

An key risk signal is acute pain. Contrarily, chronic pain is a result of a lingering injury and can even occur in the absence of a stimulation, injury, or illness. Despite affecting hundreds of millions of people, chronic pain is one of the least well-managed healthcare conditions. Development of innovative medications based on a thorough comprehension of the underlying mechanisms is essential to improving the management of chronic pain, particularly in light of the rising opioid crisis.

Project leader and co-corresponding author Shane Cronin explains, "We had previously shown that sensory neurons create a specific molecule, BH4, which then causes chronic pain, such as neuropathic pain or inflammatory pain. He works as a staff scientist at IMBA's Penninger lab and was a postdoctoral fellow at the Woolf lab at Harvard Medical School and the F.M. Kirby Neurobiology Center at Boston Children's Hospital. "The levels of BH4 showed a strong correlation with pain levels. So, we naturally concluded that this was a fantastic pathway to target.”

Green is used to depict mouse sensory neurons. The chemical BH4, which causes persistent pain, is displayed in magenta. As a result, the neurons that are "in pain" become magenta/white. Credit: IMBA/Cronin

The researchers conducted a "phenotypic screen" of 1000 target-annotated, FDA-approved medicines to find pharmaceuticals that lower BH4 levels in pain neurons. By employing drugs that are already being used for a variety of reasons as a starting point, the researchers were able to find unrecognized, off-target analgesic qualities. The researchers was able to connect the previously noted analgesic effects of various medications, including clonidine and capsaicin, to the BH4 pathway as one of the earliest findings of this hypothesis-driven search. (Capsaicin, the active ingredient in chili peppers, and clonidine, a prescription drug normally used to decrease blood pressure.)

However, Cronin adds, "Our phenotypic screen also enabled us to'repurpose' an unexpected medication." the antipsychotic medication "fluphenazine," which has been used to treat schizophrenia. In damaged nerves, fluphenazine suppresses the BH4 pathway, as we discovered. Additionally, we in vivo demonstrated its benefits on persistent pain after nerve injury. The researchers also discovered that fluphenazine's effective analgesic dose in their mouse model studies was comparable to the low end of the safe doses recommended for schizophrenia in people.

Additionally, a fresh and unexpected molecular connection between the BH4 pathway and the EGFR/KRAS signaling pathway, which is involved in numerous malignancies, was discovered by the screen. By lowering BH4 levels, blocking EGFR/KRAS signaling decreased pain sensitivity. The two most often mutated genes in lung cancer are EGFR and KRAS, which is what led the researchers to look at BH4 in lung cancer. Surprisingly, the mice models of KRAS-driven lung cancer produced fewer tumors and lived far longer by deleting an essential enzyme, GCH1, in the BH4 pathway. As a result, the study team discovered a shared signaling pathway between lung cancer and chronic pain through EGFR/KRAS and BH4, offering up fresh therapy options for both diseases.

Palliative treatments for chronic pain are currently used, however they are frequently ineffective. Additionally, if taken improperly, powerful medications like opioids can cause severe addiction. In order to manage chronic pain, it is crucial to discover and create new and repurposed medications, according to co-corresponding author Clifford Woolf, professor of neurology and neurobiology at Harvard Medical School and head of the F.M. Kirby Neurobiology Center at Boston Children's Hospital.

The study's mechanistic analysis of the relationship between pain and lung cancer is noteworthy. "It appears that the same factors that promote tumor growth also contribute to the development of the chronic pain that cancer patients frequently suffer. According to co-corresponding author Josef Penninger, "We also know that sensory nerves can fuel cancer, which may explain the vicious cycle between cancer and pain. In addition to serving as the director of the Life Sciences Institute at the University of British Columbia (UBC), Vancouver, Canada, he is an IMBA group leader and founding director. Understanding these cross-talks is therefore crucial for cancer treatments and may also help cancer patients live better lives with less pain.

Harvard Medical School, the Canadian Institutes of Health Research, the Harvard Stem Cell Institute, the City of Vienna, the Austrian Science Fund, the Austrian Academy of Sciences, the National Institutes of Health, and the T. von Zastrow foundation are among the organizations that have provided funding.

By INSTITUTE OF MOLECULAR BIOTECHNOLOGY