Researchers explore the brain’s ‘cleanup crew’ for non-opioid pain relief

Chronic pain is a daily reality for millions of Americans, interfering with their everyday activities and quality of life. An estimated 24.3% of adults in the United States experienced chronic pain in 2023, and current treatment options are not always effective. But new research from the Texas A&M University Health Science Center (Texas A&M Health) suggests the brain’s own housekeeping system could hold the key to lasting relief.

Scientists in the laboratory of Shashank M. Dravid, PhD, in the Department of Psychiatry and Behavioral Sciences at the Texas A&M University Naresh K. Vashisht College of Medicine are working to understand the link between chronic pain and autophagy, the cell’s cleanup crew.

The role of the central amygdala in chronic pain

Dravid’s research group focuses on understanding the communication pathways between distinct neurons within the central amygdala, a key region of the brain involved in processing emotional and sensory information. This area plays a pivotal role in modulating pain perception and affective responses. Deciphering how neurons within this network communicate offers critical insights into the mechanisms underlying chronic pain.

Neurons communicate by sending electrical and chemical signals across tiny gaps known as synapses. At these synapses, the signals are received by specialized receptor proteins on the neighboring neuron. These receptors act like molecular “gateways,” converting chemical messages back into electrical or biochemical signals within the receiving cell.

The brain’s ability to change and adapt, known as plasticity, depends in part on how these receptors are added to or removed from the cell’s surface. Previous research in the Dravid lab demonstrated the role of glutamate receptor delta-1 (GluD1) in chronic pain, and Dravid’s team has been expanding upon these findings.

The GluD1 protein, along with two other proteins called cerebellin-1 (Cbln1) and neurexin-1α (Nrxn1α), connect to form a “bridge” across the synapse, allowing neurons to communicate. This most recent study from the Dravid group shows that the breakdown of this bridge results in the loss of autophagic flux.

“As we continue to explore the connection between autophagy in chronic pain, we learn more about the role of GluD1 as a regulating force,” said Kishore Kumar S. Narasimhan, a postdoctoral research associate in the Dravid lab and the lead author in this study.

While the GluD1-Cbln1-Nrxn1α transsynaptic bridge was reduced in the central amygdala, the researchers saw a rise in two subtypes of the AMPA receptors (short for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and in the strength of their signals. These receptors act like the volume control for pain: When their activity increases, pain gets louder; when it decreases, the pain quiets down.

“There are two main types of synaptic plasticity: long-term potentiation (LTP) and long-term depression (LTD),” said Poojashree Chettiar, a PhD candidate in Dravid’s Lab and the second author who contributed the electrophysiological findings for this study. “In pain conditions, the balance shifts toward potentiation, leading to increased neuronal excitability. In contrast, long-term depression acts as a natural inhibitory mechanism that helps dampen pain signaling. Increased AMPA signal weakens the LTD, which helps reduce pain.”

Cleaning up the signal

The scientists wanted to understand why AMPA receptors became more abundant and active during pain. They discovered that in pain models, autophagy decreased in the central amygdala, specifically in neurons that preferentially express GluD1.

Autophagy clears out old, damaged or redundant cell parts and recycles the materials to build new cellular components. Dravid’s team found that when GluD1-Cbln1 transsynaptic signaling was disrupted, this cleanup process slowed, and pain increased as a result.

With less cleanup happening, fewer AMPA receptors were cleared away, leading to a buildup of these receptors on the surface of the cells. This, in turn, made pain signals louder.

“We identified that GluD1 regulates autophagy, but we didn’t know the mechanism. In this paper, we identified that GluD1 directly associates with autophagic mediators such as Beclin-1 and LAMP1, and that’s how it regulates the autophagic process,” Narasimhan and Chettiar said.

A novel peptide approach

The team has developed a novel peptide therapy designed to restore cell signaling, reactivate autophagy and ultimately reduce chronic pain.

Building on their discovery that GluD1 interacts with proteins that coordinate the cell’s autophagic cleanup, the Dravid lab realized that mimicking the GluD1 protein might jumpstart the cell’s natural cleanup process, potentially leading to reduced pain. Prior research implicated a portion of the GluD1 protein’s c-terminus as a target for regulating AMPA receptor plasticity.

“We have developed a small peptide based on the c-terminal of GluD1, which we are proposing as a drug modulator for chronic pain,” Narasimhan said.

This specially designed peptide, called Tat-HRSPN, mimics the GluD1 protein c-terminal region. When tested in an animal model of pain, Tat-HRSPN reduced pain within 48 hours and remained effective throughout the seven-day test period. Furthermore, the treatment increased autophagy and decreased AMPA receptors and their activity. By treating with this novel peptide, the Dravid research group was able to reduce pain and fix the breakdown in the cell’s cleanup process.

What’s next

The Dravid group plans to build on these early results by studying how long the treatment remains effective and how it can be translated into clinical applications. Their long-term goal is to develop a targeted, non-opioid therapy that could transform pain management.

“Current treatments for chronic pain often rely on opioids, which carry the risk of addiction and limited long-term efficacy,” Dravid said. “Our findings open the door to a new class of precision therapies that act directly on neural circuits involved in pain processing. If successful, this approach could fundamentally change how we manage chronic pain and significantly improve the quality of life for millions of patients.”

This discovery marks a pivotal step toward reimagining chronic pain therapy, shifting the focus from symptom suppression to restoring the brain’s natural repair pathways. By uncovering how synaptic communication and cellular recycling intertwine in the amygdala, the team has provided a blueprint for precision, non-opioid interventions that harness the brain’s own resilience. It’s a vision where pain management moves beyond relief, toward true neural recovery.

By Danielle Michaud, Texas A&M University Health Science Center