Search

Locally Administered Lipidated Peptides Offer Long-Lasting Pain Relief without Opioids - Genetic Engineering & Biotechnology News

An investigation into the mechanisms involved in pain sensation has led to the development of a novel and potentially durable treatment for inflammatory pain that could offer a promising alternative to opioid drugs. The preclinical research, conducted by neuroscientists and pharmacologists at the University at Buffalo (UB) Jacobs School of Medicine and Biomedical Sciences, showed that administration of specific lipidated peptide molecules—peptides modified with lipid molecules—to the site of pain, blocked nociceptor endocytosis, and significantly reduced acute and chronic pain-like behaviors and provided prolonged analgesia.

“Our small peptides are able to penetrate nerve endings and provide long-lasting pain relief after a single administration,” said Arin Bhattacharjee, PhD, who is associate professor of pharmacology and toxicology in the Jacobs School, and senior author of the team’s published paper in Nature Communications, which is titled, “Inhibiting endocytosis in CGRP+ nociceptors attenuates inflammatory pain-like behavior.”

UB has filed patents on two sets of novel lipidated peptides that are injected at the site of injury. With the assistance of UB Business and Entrepreneurial Partnerships, the researchers have also formed a startup company, Channavix, which is developing non-opioid drugs for pain, to assist in commercialization.

The UB researchers had been investigating sensory neurons called nociceptors, which activate in response to pain caused by injury. “Pain is usually considered a symptom of injury,” said Bhattacharjee. “Pain neurons transmit their information to the brain, informing the brain of both the location of the injury and the severity of the injury.” The authors further explained, “Peripheral sensitization of dorsal root ganglion (DRG) nociceptors initiates inflammatory pain and is driven by inflammatory mediators released from immune cells and damaged tissue.”

Calcitonin gene-related peptide (CGRP)-containing nociceptors had also previously been identified as the principal coordinators of thermal and mechanical sensitivity in various pain models, the team continued. “Therefore, it is reasonable to consider CGRP+ nociceptors as potential analgesic targets,” they wrote. Bhattacharjee and first author Rasheen Powell, PhD, who is currently a postdoctoral fellow in the department of neurology at Harvard Medical School, had discovered that in order to signal pain, these CGRP-containing pain neurons require endocytosis, the process by which cells engulf external materials or materials at the membrane. They had found that the CGRP+ neurons preferentially express a specific endocytosis subunit called AP2A2, which other sensory neurons do not. “Previously, we have shown that AP2 clathrin-mediated endocytosis (AP2-CME) underlies DRG neuronal sensitization through internalization of sodium-activated potassium channels (KNa) in vitro and that the AP2α2 subunit becomes associated with these channels after protein kinase A (PKA) stimulation.” However, they added, “Whether extra-synaptic endocytosis in DRG neurons is required for pain initiation and pain maintenance have yet to be addressed.”

In their newly reported research, the researchers describe how they found that this process of endocytosis in these neurons was, indeed, essential for both the development and maintenance of inflammatory pain.

The team investigated the effects of pharmacologically inhibiting endocytosis in peripheral nociceptor neurons during inflammation, using a small lipidated inhibitor peptide. These experiments demonstrated that a single administration of the peptide in a rodent model resulted in significantly reduced behaviors associated with inflammatory pain. Powell said, “… when we inhibit endocytosis with either a genetic or pharmacological approach, we observe profound reductions in behaviors indicative of pain.” Added the authors, “We utilized genetic and pharmacological approaches to inhibit nociceptor endocytosis demonstrating its role in the development and maintenance of acute and chronic inflammatory pain.”

And even under conditions that promote hyperactivity in pain neurons, the researchers found they could significantly reduce this hyperactivity—and therefore pain perception—when they prevented endocytosis with the novel peptide molecule. “By inhibiting endocytosis, we are able to prevent pain-sensing neurons from relaying pain information to the central nervous system,” said Powell.

“At the molecular level, our research is helping unravel how tissue injury signals to pain-sensing neurons,” Bhattacharjee noted. “If we can understand this at the molecular and cellular level, we can then identify novel pain-killing targets.” Added Powell, “This finding is particularly exciting because a specific subset of pain neurons in the DRG in the peripheral nervous system expresses AP2A2 while other populations of sensory neurons in the DRG do not. This suggests that this subunit has an important role in these particular pain neurons, which are responsible for a majority of inflammatory pain behaviors observed in rodents and humans.”

A key advantage of the peptides developed by the researchers is that they disrupt endocytosis when applied locally at pain nerve endings. “In clinical practice, we use local approaches all the time to block pain,” said Bhattacharjee. “Anesthetics are effective at blocking pain but the problem is, they block all sensory neurons, so the patient feels numb, and they are very short-lived. After the anesthetic wears off in a few hours, painkillers are often needed. “We found that when locally applied, our peptide decreased pain behaviors in multiple inflammatory pain models for up to six days.”

The advantage of locally delivered drugs is that most adverse side effects are avoided, especially the risk of addiction. Adverse side effects are also a key reason why new drugs often fail to achieve FDA approval. Local delivery of drugs avoids that downside.

Bhattacharjee also noted that while locally delivered drugs tend to diffuse away quickly from the site to which they were originally administered, “Our novel technology seems to solve this problem by getting into nerve endings and staying there. The result is a long-lasting reduction in pain behavior.” As the authors noted, “…we have demonstrated locally administered lipidated peptidomimetics are able to produce specific and long-lasting reductions in pain-like behaviors.”

The UB research also found that males and females experience pain differently. In two models of pain, assessed through rodent studies, they discovered that if the pain was already established, female animals did not respond as well to the peptide compared with males. But if the peptide was administered right at the time of injury, females had a much better reduction in pain behavior than did their male counterparts. “… the sex-dependent difference was contingent on whether the AP2 inhibitor peptide was given before or after development of inflammation,” the authors wrote. “In both inflammatory pain models, we have observed a sexually dimorphic response to both injury and our peptidomimetic suggesting that males experience a more complete analgesia, compared to females, with peripherally acting compounds after inflammation is established … In a situation where pre-emptive analgesia is desired, females appear to respond better than males.”

“These data follow human clinical studies,” said Bhattacharjee, “where there is a sex difference in both the prevalence and intensity of chronic inflammatory and postoperative pain in humans. This underscores the importance of gender considerations in analgesic development.” As the authors stated, “Our data is consistent with the idea that there are sex differences in both the prevalence and the intensity of chronic inflammatory and postoperative pain in humans.”

The researchers plan to focus on key preclinical formulation and toxicology studies to enable a new Investigational Drug Application to start human testing.

Adblock test (Why?)



"lasting" - Google News
October 05, 2021 at 03:00PM
https://ift.tt/3a81vqp

Locally Administered Lipidated Peptides Offer Long-Lasting Pain Relief without Opioids - Genetic Engineering & Biotechnology News
"lasting" - Google News
https://ift.tt/2tpNDpA
Shoes Man Tutorial
Pos News Update
Meme Update
Korean Entertainment News
Japan News Update

Bagikan Berita Ini

0 Response to "Locally Administered Lipidated Peptides Offer Long-Lasting Pain Relief without Opioids - Genetic Engineering & Biotechnology News"

Post a Comment

Powered by Blogger.