Opioids have been a standard treatment for pain for thousands of years. Canonical forms like morphine have been administered since the early nineteenth century due to their high efficacy in reducing the emotional component of pain. However, opioids also carry risks, such as dependence and respiratory depression, limiting their therapeutic potential for chronic pain. Researchers hope that uncovering the mechanism behind opioids’ pain-relieving effects will lead to new therapeutic strategies. Designing alternative therapies for pain involves further investigation of the interaction between opioids’ target neurons and the neural circuits that mediate pain in the brain.
A recent study published in Nature by researchers from the University of Pennsylvania revealed that opioids do not relieve pain by simply repressing the activity of pain-related neurons. “There is a broader circuit effect that we’re not understanding fully and hope to disentangle,” said Corinna Oswell, a co-lead author of the study. The team engineered an opioid-mimicking gene therapy targeting opioid-sensitive neurons, providing a promising alternative to conventional opioids that reduces the risk of dependence and unwanted suppression of the respiratory system.
The targeting mechanism involved packaging genetic material into a virus that tricked the subject’s neurons into producing a protein with the same fundamental structure as an opioid receptor. This interacts with a co-administered drug, deschloroclozapine (DCZ), that normally has no natural target in the body. The gene therapy aimed to reproduce pain relief by targeting only the anterior cingulate cortex (ACC), a major pain-active region of the brain that significantly contributes to the emotional component of pain.
This contrasts with traditional opioids, which circulate throughout the body and brain and can thereby produce off-target effects. For instance, opioids can act in the ventral tegmental area to induce dopamine release in the nucleus accumbens and promote addiction. “[Local opioid action in the ACC] is not particularly linked to dependence, but it is heavily linked to pain relief,” Oswell said. The team’s localized delivery of the gene therapy to the ACC is designed to promote pain relief while minimizing other opioid effects like addiction and respiratory depression. Notably, this therapy is safer than simply restricting traditional opioids to specific areas of the brain because the DCZ drug only interacts with proteins produced by the gene therapy. As such, the treatment could be handled and distributed with minimal risk, as individuals who have not received the therapy would experience no pharmacological effects.
Experiments in mice confirmed the efficacy of the gene therapy as a prospective treatment for chronic pain, with similar levels of pain relief as seen in mice treated with morphine. The team is currently fine-tuning the treatment by assessing its efficacy and potential side effects, including immunoreactivity from prolonged viral expression in the brain. Additionally, the researchers are testing the therapy in non-human primate models. Using highly conscious subjects, it is paramount that the preliminary experiments show considerable promise to avoid unjustified pain. “Pain is a difficult thing to study, so there has to be significant justification,” Oswell said. While further research is needed to confirm its safety and efficacy, the results demonstrate the substantial potential of this biology-inspired opioid gene therapy as a novel treatment for chronic pain.