Chemical Biology and Bioengineering Approaches for Probing the Pathways to Chronic Pain
Nigel W. Bunnett
NYU, College of Dentistry
Acute pain is an evolutionarily conserved sensation that is necessary for survival because it allows the avoidance of danger and the awareness of injury. When dysregulated, pain becomes chronic, debilitating, and a major cause of suffering. The mechanisms that underlie the transition from acute to chronic pain are poorly understood. Consequently, existing therapies are inadequate or have unacceptable side effects. The magnitude of the problem is illustrated by the opioid crisis, where death by overdose, principally of opioids, accounts for >70,000 deaths annually in the USA.
This presentation concerns the role of G protein-coupled receptors (GPCRs) as mediators and therapeutic targets for chronic pain. With almost 1,000 members in humans, GPCRs are the largest family of receptors, control most physiological and pathological processes, and are the target of >33% of FDA-approved drugs. GPCRs are key mediators of pain. GPCRs are highly dynamic proteins that adopt different conformations and subcellular distributions upon activation. The presentation will discuss how an understanding of the dynamic properties of GPCRs can provide a deeper insight into the mechanisms of pain chronification and reveal new opportunities for therapy. Chemical biology approaches can be harnessed to develop probes to detect key mediators of pain and to block critical steps in the pain pathway. Nanomedicines can be designed to deliver GPCR antagonists and agonists to subcellular domains of neurons that sense and transmit pain, increasing efficacy. These approaches offer the possibility of developing new drugs to treat pain that are devoid of the unacceptable side effects of opioids.