University at Buffalo researchers have developed a breakthrough non-opioid molecule that acts as a long-lasting local anesthetic, providing robust chronic pain relief for up to three weeks with a single injection. The preclinical findings, published in the journal Pain, represent a significant advancement in pain management that could offer an alternative to opioid-based treatments.
Novel Mechanism Targets Pain-Specific Pathways
The new molecule employs a unique approach by targeting Magi-1, a scaffolding protein that brings specific proteins together at locations within the cell membrane. Unlike traditional local anesthetics that block both pain and touch sensations indiscriminately, this targeted therapy specifically disrupts pain transmission pathways.
"Local anesthetics dramatically changed health care when first introduced into clinical practice during the turn of the 20th century," explains Arin Bhattacharjee, PhD, professor of pharmacology and toxicology in the Jacobs School of Medicine and Biomedical Sciences at UB and senior author on the paper. "The limitation with local anesthetics is that they aren't very selective for your pain fibers — they block touch sensation as well — and they don't last very long. In our new paper we showed how our new molecule acts like a local, long-lasting pain-fiber anesthetic."
Disrupting the Magi-1/NaV1.8 Interaction
The therapeutic strategy focuses on the interaction between Magi-1 and NaV1.8, an ion channel crucial for pain transmission. While the FDA recently approved a drug that directly blocks NaV1.8 channels for acute pain, that approach has shown limited success for chronic pain conditions.
"We had previously shown that Magi-1 scaffolds NaV1.8 and, importantly, protected these channels from degradation," Bhattacharjee explains. "Without Magi-1, NaV1.8 channels become degraded. So our approach is to target this scaffold-ion channel interaction."
The new molecule is a lipidated peptide — a peptide modified with lipid molecules based on the part of the NaV1.8 channel that interacts with Magi-1. This "decoy" peptide outcompetes NaV1.8 channels for binding to Magi-1, leaving the pain-transmitting channels exposed to degrading enzymes.
Extended Duration Through Membrane Anchoring
The lipid modification serves a dual purpose in the molecule's design. The lipid component allows the peptide to anchor within the neuronal membrane and penetrate inside the cell, while also providing protection from extracellular proteases that would normally degrade peptides.
"The added benefit is once the lipidated peptide is anchored within the neuronal membrane, it is protected from extracellular proteases," Bhattacharjee notes. "We saw weeks of pain relief because it takes weeks to clear the lipidated peptide from the neuronal membrane."
Validation in Human Neurons
To ensure clinical relevance, the research team validated their approach using human pain neurons. "So we needed to make sure that the decoy peptide works similarly in humans," says Bhattacharjee. "If it didn't, it would not be a potential drug. Fortunately, we showed that targeting the scaffolding of NaV1.8 channels in human pain neurons also worked with a lipidated decoy peptide."
Path to Clinical Development
The research team is now preparing for toxicity trials as the next step toward clinical development. Bhattacharjee anticipates minimal toxicity concerns due to the local injection approach, noting that "it's not a systemic drug — i.e., a drug that goes all throughout your body and can deposit into your organs."
Bhattacharjee is co-founder of startup company Channavix Therapeutics LLC, which is working to commercialize these non-opioid pain relievers. The team is actively seeking partners to advance the peptide to clinical trials.
The research was conducted by a collaborative team including co-authors Molly K. Martin, PhD, from the University of Massachusetts Chan Medical School; Rasheen Powell, PhD, from the Kirby Neurobiology Center at Boston Children's Hospital; Raider Rodriguez, PhD, and Garrett Sheehan, PhD, from Stanford University; Amanda H. Klein, PhD, associate professor at UB; and Giselle Guerrero from Bhattacharjee's laboratory.
The work was supported by a grant from the National Institutes of Health's HEAL Initiative, which focuses on developing science-based solutions to the opioid crisis.
