Tag Archives: #chronicpain

New Study Further Advances the Treatment of Chronic Pain (Medicine)

LIH and RTI International put forward the mode of action of natural painkiller conolidine, and develop new molecule with enhanced pharmacological properties 

Building on their previous findings, scientists from the Immuno-Pharmacology and Interactomics group at the Department of Infection and Immunity of the Luxembourg Institute of Health (LIH), in collaboration with the Center for Drug Discovery at RTI International (RTI), a nonprofit research institute, have demonstrated that conolidine, a natural painkiller derived from the pinwheel flower and traditionally used in Chinese medicine, interacts with the newly identified opioid receptor ACKR3/CXCR7 that regulates opioid peptides naturally produced in the brain. The researchers also developed a synthetic analogue of conolidine, RTI-5152-12, which displays an even greater activity on the receptor. These findings, which were published on June 3rd in the prestigious international journal ‘Signal Transduction and Targeted Therapy’ (Nature publishing group), further advance the understanding of pain regulation and open alternative therapeutic avenues for the treatment of chronic pain. 

Opioid peptides are small proteins that mediate pain relief and emotions, including euphoria, anxiety, stress and depression, by interacting with four classical receptors (“molecular switches”) in the brain. Dr Andy Chevigné, Head of Immuno-Pharmacology and Interactomics, and his team had previously identified the chemokine receptor ACKR3 as a novel fifth atypical opioid receptor, with high affinity for various natural opioids (Nature Communications, Meyrath et al. 2020). ACKR3 functions as a ‘scavenger’ that ‘traps’ the secreted opioids and prevents them from binding to the classical receptors, thereby dampening their analgesic activity and acting as a regulator of the opioid system.

In the current study, the researchers identified ACKR3 as the most responsive target for conolidine, an alkaloid with analgesic properties, by screening over 240 receptors for their ability to be activated or inhibited by this molecule.

We confirmed that conolidine binds to the newly identified opioid receptor ACKR3, while showing no affinity for the other four classical opioid receptors. By doing so, conolidine blocks ACKR3 and prevents it from trapping the naturally secreted opioids, which in turn increases their availability for interacting with classical receptors. We believe that this molecular mechanism is at the basis of the beneficial effects of this traditionally used medicine on pain relief”, said Dr Martyna Szpakowska, first author of the publication and scientist within the LIH Immuno-Pharmacology and Interactomics group.

In parallel to characterising the interaction between conolidine and ACKR3, the two teams went a step further. The scientists developed a modified variant of conolidine — which they called “RTI-5152-12” — which exclusively binds to ACKR3 with an even higher affinity. Like LIH383, a patented compound previously developed by Dr. Andy Chevigné and his team, RTI-5152-12 is postulated to increase the levels of opioid peptides that bind to classical opioid receptors in the brain, resulting in heightened painkilling activity. The LIH-RTI research teams established a collaboration agreement and filed a joint patent application in December 2020.

The discovery of ACKR3 as a target of conolidine further emphasises the role of this newly discovered receptor in modulating the opioid system and, consequently, in regulating our perception of pain”, said Dr. Chevigné, corresponding author of the publication and leader of the LIH Immuno-Pharmacology and Interactomics group.

Our findings could also mean that conolidine, and potentially also its synthetic analogues, could carry new hope for the treatment of chronic pain and depression, particularly given the fact that conolidine was reported to trigger fewer of the detrimental side-effects — namely addiction, tolerance and respiratory problems —  associated with commonly used opioid drugs like morphine and fentanyl”.

Our work could therefore set the basis for the development of a new class of drugs with alternative mechanism of action, thereby contributing to tackling the public health crisis linked to the increasing misuse of and addiction to opioid drugs”, says Dr. Ojas Namjoshi, co-corresponding author of the publication and lead scientist on the study at RTI.

Once again, we have built on the findings of our excellent fundamental research and translated them into applications with the potential of tangibly improving clinical outcomes for patients”, said Prof Markus Ollert, Director of the LIH Department of Infection and Immunity. “We are grateful to the Luxembourg National Research Fund, the Ministry of Higher Education and Research and the European Commission for the generous support”.   


FUNDING AND RESEARCH TEAMS

This study was supported by funds from the Luxembourg Institute of Health (LIH), the Luxembourg National Research Fund (Pathfinder “LIH383”, INTER/FWO “Nanokine” grant 15/10358798, INTER/FNRS grants 20/15084569, PoC “Megakine” 19/14209621, PRIDE 11012546 “NextImmune” and 14254520 “I2TRON”), F.R.S.-FNRS-Télévie (grants 7.4593.19, 7.4529.19 and 7.8504.20) and by RTI International Internal Research and Development Funds (awarded to O. Namjoshi). M. Meyrath and C. Palmer are Luxembourg National Research Fund PhD fellows (grants AFR-3004509 and AFR-14616593). C. Palmer is part of the Marie Skłodowska-Curie Actions – Innovative Training Networks ONCORNET2.0 “ONCOgenic Receptor Network of Excellence and Training” (MSCA-ITN-2020-ETN). The authors wish to thank Manuel Counson for technical assistance in binding competition experiments.

The study was performed in close collaboration with the Center for Drug Discovery of RTI International (USA).


Reference: Szpakowska, M., Decker, A.M., Meyrath, M. et al. The natural analgesic conolidine targets the newly identified opioid scavenger ACKR3/CXCR7. Sig Transduct Target Ther 6, 209 (2021). https://doi.org/10.1038/s41392-021-00548-w


Provided by Luxembourg Institute of Health

Scientists Find New Cell Type Implicated in Chronic Pain, Inflammation (Medicine)

The discovery, from the UNC School of Medicine lab of Mark Zylka, PhD, offers pain researchers a new, precise target to treat inflammation associated with neuropathic pain.

One of the hallmarks of chronic pain is inflammation, and scientists at the UNC School of Medicine have discovered that anti-inflammatory cells called MRC1+ macrophages are dysfunctional in an animal model of neuropathic pain. Returning these cells to their normal state could offer a route to treating debilitating pain caused by nerve damage or a malfunctioning nervous system.

The researchers, who published their work in Neuron, found that stimulating the expression of an anti-inflammatory protein called CD163 reduced signs of neuroinflammation in the spinal cord of mice with neuropathic pain.

“Macrophages are a type of immune cell that are found in the blood and in tissues throughout the body. We found a class of anti-inflammatory macrophages that normally help the body to resolve pain. But neuropathic pain appears to disable these macrophages and prevent them from doing their job,” said senior author Mark Zylka, PhD, director of the UNC Neuroscience Center and Kenan Distinguished Professor of Cell Biology and Physiology. “Fortunately they don’t appear to be permanently disabled, as we were able to coax them to ramp up their anti-inflammatory actions and reduce neuropathic pain. We suspect it will be possible to develop new treatments for pain by boosting the activities of these macrophages.”

Mark Zylka, PhD

Roughly one-fifth of the U.S. population has chronic pain, according to the Centers for Disease Control and Prevention. Often the underlying causes are elusive, and patients need pain alleviated so they can function in life. While opioids are great at treating pain in the short term, these drugs can have severe side effects when used for extended periods, such as addiction, respiratory depression, dizziness, nausea, and death due to overdose.

One reason why strong pain relievers work well but can have dramatic side effects has to do with a basic biological fact: pain involves a highly diverse set of cells and current treatments lack cell type specificity. So, any given medication may resolve adverse changes in some cells to alleviate pain, but the medication might exacerbate a particular function in other cells, leading to adverse side effects.

With an emerging technology called single-cell RNA-sequencing, scientists can now interrogate thousands of cells at once to see which cells are altered during chronic pain, and in which ways the cells change.

Jesse Niehaus

“Knowing which cells to target allows us to design very specific therapies. Targeted therapies in theory should have fewer adverse side-effects,” said Jesse Niehaus, graduate student in the Zylka lab and first author of the Neuron paper.

To figure out which cells were changing and in what ways, Zylka’s lab performed single-cell RNA-sequencing on the spinal cords of mice with neuropathic pain, a type of chronic pain caused by nerve damage. The spinal cord undergoes many long-term changes that contribute to neuropathic pain.

From those experiments, the researchers found a population of anti-inflammatory cells called MRC1+ macrophages that were dysfunctional.

“This was incredibly interesting because long-term inflammation in the spinal cord is commonly seen in animals with neuropathic pain,” Niehaus said.

With the identity of the cells revealed, Zylka’s lab delivered a gene therapy designed to stimulate the expression of an anti-inflammatory protein called CD163 in MRC1+ macrophages. With this approach, a single treatment reduced spinal cord inflammation and relieved pain-related behavior for up to a month.

“This discovery is quite exciting,” Zylka said, “As it immediately suggests multiple distinct ways to boost the function of these macrophages. Any one of these therapeutic approaches could provide a more precise way to treat neuropathic pain.”

Other authors of the Neuron paper are Jeremy Simon, PhD, research assistant professor; Bonnie Taylor-Blake, research specialist, and Lipin Loo, PhD, a former postdoc in the Zylka Lab who is now a research fellow at the University of Sidney.

The National Institute of Neurological Disorders and Stroke funded this research. Sequencing was performed at the UNC High Throughput Sequencing Core. Microscopy was performed at the UNC Neuroscience Center Microscopy Core.

Featured image: Spinal cord illustration of pro-inflammatory cells (red) and anti-inflammatory MRC1+ macrophages (blue).


Reference: Jesse K. Niehaus, Bonnie Taylor-Blake et al., “Spinal macrophages resolve nociceptive hypersensitivity after peripheral injury”, Neuron, 2021. DOI: https://doi.org/10.1016/j.neuron.2021.02.018


Provided by UNC School of Medicine