By Clifford Woolf

Given the opioid crisis, managing pain effectively with drugs that have no abuse liability is an urgent societal need. So far industry has not had much success in coming up with potent non-opioid analgesics, and indeed this is not a high priority for many pharmaceutical companies since it has proven to be both difficult and expensive.  This has shifted the burden of such discoveries to academic institutions, and I am very proud to be a member of a Harvard Medical School and Boston Children’s Hospital Panacea Consortium sponsored by DARPA, devoted to discovering novel effective and safe analgesics, working together in close collaboration with Bruce Bean, Mark Namchuk and Peter Sorger and their teams, as well as with the National Center for Advancing Translational Sciences at the NIH.

To do this, we have developed an analgesic discovery platform that is designed to identify drugs that will selectively silence only those sensory neurons that trigger pain (nociceptors – noxious stimulus detecting neurons) and have no or minimal activity on any other excitable cells/neuron. To achieve this, we have identified that a polypharmacological approach acting on multiple targets works better than the industry standard single target strategy. The platform includes a means of screening hundreds of thousands of compounds against the multiple targets, validation of the hits with an automatic patch clamp system, testing silencing efficacy on both mouse and human stem cell derived nociceptors with counter screens showing no activity on human cortical and motor neurons or cardiomyocytes, and finally in vivo detection of analgesia without adverse effects using a machine learning paradigm to interrogate nociceptor driven behavioral changes indicative of pain in freely moving mice. Development of this platform involved identifying a high throughput ion flux readout assay, mastering automatic patch clamp in 384 wells, developing effective sensory neuron differentiation protocols and human phenotypic assays, and designing a new instrument to measure mouse behavior and the algorithms to automatically analyze this.

Once we identify a promising scaffold from the platform, a medicinal chemistry program is initiated to increase potency and target selectivity as well as drug-like physicochemical properties. We now have several compounds that act on 2 or 3 targets and have good analgesia efficacy profiles (better than drugs that only act on one target) with minimum changes indicative of sedation or altered locomotion. We can now also test if these hits don’t act on those receptors that drive abuse liability like cannabinoid 1, dopamine receptors and the mu opioid receptor, and do not elicit pathological self-administration in vivo. If successful we may be able, at last, to abandon prescription opioids and provide pain patients with better treatment with fewer side effects.

Clifford Woolf is Director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and Professor of Neurology and Neurobiology at Harvard Medical School.

Learn more in the original article:
Pain researchers must learn from the opioid crisis.
Woolf C. Nature. 2024 Sep;633(8031):S40