New, non-opioid molecule acts like a long-lasting anesthetic, relieving chronic pain for three weeks

BUFFALO, N.Y. – A new molecule developed by University at Buffalo researchers acts like a local, long-lasting anesthetic, providing robust pain relief for up to three weeks, according to the results of preclinical studies reported recently in the journal Pain.

Like the numbing sensation we are all familiar with when we get anesthetized at the dentist’s office, the new molecule acts like a local anesthetic, but in a much more targeted way.

“Local anesthetics dramatically changed health care when first introduced into clinical practice during the turn of the 20th century,” says 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. We showed that a single injection locally can relieve chronic pain behavior for three weeks.”

Bhattacharjee is co-founder of the startup company Channavix Therapeutics LLC, which is working to commercialize these non-opioid pain relievers developed in his lab.

Targeting a key interaction

The new molecule targets a protein called Magi-1, a scaffolding protein that brings specific proteins together at specific locations within the cell membrane. One of the proteins it interacts with is NaV1.8, an ion channel that plays an important role in transmitting pain.

Earlier this year, Bhattacharjee points out, the Food and Drug Administration approved a drug that blocks the NaV1.8 ion channels to treat acute pain.

“This was a breakthrough because a new pain-targeted drug had not been developed for many years,” he says. “Unfortunately, that drug seems to only work for acute, post-surgical pain. It has yet to show success for chronic pain.”

The new molecule addresses pain through a different approach: Instead of blocking the NaV1.8 channels, the new drug targets the interaction that these pain-transmitting ion channels have with the Magi-1 scaffolding protein.

“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 and based on the part of the NaV1.8 channel that interacts with Magi-1. Bhattacharjee says it acts like a “decoy” peptide.

“When this decoy peptide is introduced into pain neurons, it outcompetes NaV1.8 channels binding to Magi-1,” he continues. “The ‘liberated’ NaV1.8 channels are now left exposed as they become targets for degrading enzymes.”

Once degraded, the NaV1.8 ion channels can’t function properly to transmit pain.

Putting a lipid onto the peptide allows it to anchor within the neuronal membrane and then penetrate inside, Bhattacharjee explains. “The added benefit is once the lipidated peptide is anchored within the neuronal membrane, it is protected from extracellular proteases. Proteases are enzymes that chew up peptides. We saw weeks of pain relief because it takes weeks to clear the lipidated peptide from the neuronal membrane.”

Human neurons

The team’s ultimate goal is to use this lipidated peptide to treat chronic pain in humans. “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.”

The next step is to begin toxicity trials. “Since we are locally injecting the peptide, we believe toxicity will be minimal,” says Bhattacharjee. “It’s not a systemic drug — i.e., a drug that goes all throughout your body and can deposit into your organs. We are looking for partners to help us take the peptide to clinical trials.”

Co-authors with Bhattacharjee include Molly K. Martin, PhD, a postdoctoral associate at the University of Massachusetts Chan Medical School; Rasheen Powell, PhD, of the Kirby Neurobiology Center at Boston Children’s Hospital; Raider Rodriguez, PhD, and Garrett Sheehan, PhD, of Stanford University, all of whom earned their doctorates in neuroscience at UB under Bhattacharjee.

Additional co-authors are Amanda H. Klein, PhD, associate professor of pharmacology and toxicology at UB, and Giselle Guerrero, who did research in Bhattacharjee’s lab.

The work was supported by a grant from the National Institutes of Health’s HEAL Initiative, focused on developing science-based solutions to the opioid crisis.