Opioids are still centerstage in severe pain management, despite their poor safety profiles and high potential for abuse that claims nearly 145 lives every day in the U.S. alone.

NSAIDS (nonsteroidal anti-inflammatory drugs such as ibuprofen or paracetamol) are popular painkillers but are only effective in mild pain. There is an unmet need for safe and effective analgesics to treat the spectrum of pain.

Although the analgesic property of cannabinoid compounds has been widely recognized in chronic and severe pain related to migraine, rheumatoid arthritis, osteoarthritis, neuropathy and cancer, their use has been limited due to memory loss and other cognitive impairments that arise as side effects in cannabis users.

Scientists have now built upon behavioral studies in mice that dissociate the beneficial analgesic and detrimental amnesic effects of THC (Δ9 -tetrahydrocannabinol), the main psychoactive component of Cannabis sativa, to develop peptides that allow THC to fight pain without the undesirable cognitive side effects.

These findings are reported in a Journal of Medicinal Chemistry article, Orally Active Peptide Vector Allows Using Cannabis to Fight Pain While Avoiding Side Effects” by an international team of researchers from Pompeu Fabra University (UPF) in Barcelona, Spain, and the University of Lisbon in Portugal.

THC subdues pain by binding to cannabinoid type 1 receptors (CB1R). But CB1Rs bind to serotonin receptors 5HT2A, causing memory loss. While the cognitive impairment caused by THC is due to the CB1R−5HT2AR complexes, the analgesic effects of THC arise solely from CB1R activation without its binding to the serotonin receptor.

Therefore, to segregate the analgesic and cognitive effects of THC-mediated activation of CB1Rs, the scientists decided to develop a ploy to prevent the interaction between the two receptors woven into the cell membrane. They designed and produced peptides toward this end that interrupt the receptor interaction so that THC can ease pain without cognitive impairments resulting from the activation of the serotonin receptor.

Earlier peptides designed to disrupt the interaction between the two receptors proved to be ungainly therapeutic leads due to their large size, low solubility, and inability to cross the blood−brain barrier.

The researchers have optimized the original peptide prototype in the current study based on molecular dynamics simulations and pharmaceutical strategies, to develop a smaller peptide with high stability that is active upon oral administration and penetrates the blood-brain barrier with ease.

Administering the peptide orally, along with an injection of THC, the authors assess pain threshold and memory capacity in mice to show reduction in pain threshold on a hotplate test and improved memory performance on an object recognition task, compared to mice treated with THC alone.

“Our results suggest that the optimized peptide is an ideal candidate for reducing the cognitive side effects of pain treatment with cannabis derivatives,” says Rafael Maldonado, PhD, Professor of Pharmacology in the Department of Experimental and Health Sciences (DCEXS) at UPF.

“Given the results obtained so far, the team is motivated to advance in the development of this promising candidate discovered,” explains David Andreu, PhD, Professor of Chemistry at UPF.

Left to right, researchers Rafael Maldonado, Maria Gallo and David Andreu [Pompeu Fabra University (UPF)]

“The INNOValora programme will allow us to partially cover the proof-of-concept experiment in chronic pain that we need to ensure investors’ participation in the project,” says Maria Gallo, a PhD student from the Proteomics and Protein Chemistry group at the DCEXS-UPF, whose doctoral thesis includes the projects experimental work.

Based on these results the group has filed an international patent application. Once the preclinical and clinical validation experiments are completed, the work will be transferred to the pharmaceutical sector.

“We envision the use of the peptide in combination with THC as the first drug approved by the EMA / FDA for the treatment of chronic pain,” says Maldonado.