According to the WHO, 30% of the population suffers from chronic pain. If acute pain can be considered a vital protective alarm, chronic pain becomes a very serious clinical problem, as the system goes into short circuit and continues to “trigger” the alert in the brain even after the body has healed.
Because the nervous system continues to send danger signals even without an active threat, the sensation of pain goes from being a symptom to becoming a debilitating neurological diseasecapable of disabling the patient, triggering deep depression and, even today, pushing thousands of people into opioid dependence.
Although they relieve pain, these potent painkillers attach their molecules to receptors spread throughout the brain. The problem is that these biological “locks” can open many unwanted doors, capable of causing chemical dependency, respiratory depression, chest stiffness, among other side effects.
Now, a group of researchers from the University of Pennsylvania, in the USA, has managed to map the exact cortical circuit through which morphine produces pain relief. Identified in the region called the anterior cingulate cortex (ACC), this specific set of neurons mediates not only the physical sensation of pain, but also the suffering it causes.
The great innovation of the study, , is the precision of the target. The gene therapy developed by the authors acts exclusively on CCA neurons that express opioid receptors. In other words, patients continue to feel pain, but the brain stops interpreting it as danger.
Tracking Chronic Pain Suffering
To map the pain circuit, researchers developed LUPE — an acronym for “automated pain evaluator” — a behavioral analysis platform based on deep learning.
It was this mapping of the cortical pain circuit that guided the development of gene therapy. The central idea is simple: instead of flooding the brain with a drug that acts on all opioid receptors, deliver just one inhibitor exclusively to the right cells — the ACC neurons that express µ-opioid receptors.
To do this, the researchers used an AAV — a virus that infects humans without causing any disease. As they have developed, throughout evolution, mechanisms to penetrate cells and deposit genetic material, genetic engineering takes advantage of this: removes what is harmful and inserts, in its place, therapeutic instruction.
The team is now working with neuroscientist Michael Platt to move towards clinical trials. “The journey from discovery to implementation is a long one, and this represents a strong first step,” says Platt. “The potential to alleviate suffering without fueling the opioid crisis is exciting,” concludes the UPenn professor.
A treatment for pain without generating dependence?
The social impact of the discovery gains relevance. Acting directly on the cortical pain circuit, without the systemic effects of traditional treatments, the approach points to a promising alternative.
For study co-senior author Gregory Corder of the University of Pennsylvania, the discovery opens a concrete path forward: “By targeting the exact brain circuits in which morphine acts, we believe this is a first step toward offering relief to people whose lives have been devastated by chronic pain,” he says in a press release.
In the process of relieving pain, opioids activate receptors distributed throughout the brain, also activating the reward system — which explains tolerance and the risk of dependence. By acting on specific neurons, the therapy developed in the study did not produce this undesirable effect.at least in tests on mice.
In practice, the mechanism acts not on the injured nerve, but on the brain — specifically on the CCA —, where pain stops being a sign of protection and becomes suffering. If confirmed in humans, the approach could reduce hospitalizations, overdoses and costs associated with long-term opioid treatments.
