The Problem and Challenges of Chronic Pain
Acute pain is protective warning mechanism that allows avoidance and awareness of injury. Injury and disease can lead to chronic pain that persists after recovery (Fig. 1). Chronic pain is a major cause of morbidity that is inadequately treated with available drugs. We study chronic pain associated with common diseases (e.g., cancer, migraine, inflammatory bowel disease, irritable bowel syndrome, pancreatitis) and injury (e.g., neuropathic pain).
Fig. 1. The transition from acute to chronic pain.
We seek to answer two major questions about chronic pain:
- How do nerve cells (nociceptors) detect painful stimuli?
- How does acute (physiological) pain become chronic (pathological)?
- How do we develop better drugs to treat chronic pain without the life-threating side effects of opioids?
G Protein-coupled receptors (GPCRs): Dynamic Machines for signaling chronic pain
Our research focuses on GPCRs, a large family of transmembrane signaling proteins that are the target of one third of therapeutic drugs. GPCRs enable neurons (nociceptors) to detect mediators from damaged and diseased tissues, and control pain transmission within the central nervous system (Fig. 2).
Fig. 2. GPCRs in the pain pathway.
GPCRs are dynamic signaling proteins (Fig. 3).
Fig. 3. GPCRs as dynamic signaling machines.
Activated GPCRs adopt different conformations and redistribute to distinct subcellular compartments. These dynamic properties explain how GPCRs control the expression of genes and activity of ion channels that mediate chronic pain.
Painful stimuli evoke endocytosis of the neurokinin 1 receptor in spinal neurons.
Endosomal platforms for substance P evoked pain transmission.
Canonical and biased agonism of protease-activated receptor-2.
New Treaments for Chronic Pain
The global opioid crisis highlights the urgent need to develop new treatments for chronic pain (Fig. 4).
Fig. 4. The opioid crisis.
Although widely prescribed, opioids are ineffective in some patients. The efficacy of opioids wanes with time and opioids can worsen pain. Their side effects of addiction, respiratory depression and constipation contribute to mortality. In 2018 over 70,000 people in the USA died from drug overdose, often opioids. We are working to develop new non-opioid treatments for pain. By using the approaches of chemical biology and biomedical engineering, we can deliver drugs to specific subcellular compartments of neurons, thereby improving effectiveness and minimizing side effects.
Experimental Tools and Approaches
We study pain at the level of the molecule, cell and animal by multiple approaches:
- Biophysical (BRET, FRET) approaches to study GPCR signaling in model cells, primary neurons and stem cell-derived human nociceptors.
- Imaging (confocal, super-resolution microscopy) approaches to evaluate GPCR trafficking in model cells, primary neurons, stem cell-derived human nociceptors, and intact tissues.
- Electrophysiological approaches to study channel regulation and nociceptor activity.
- Behavioral approaches to study nociception in experimental animals, including genetically-modified mouse models.
- Chemical biology approaches to develop probes for mediators of pain (eg, activity-based probes for proteases) and antagonists of pronociceptive GPCRs (eg, tripartite lapidated antagonists of endosomal GPCRs).
- Bioengineering approaches to generate stimulus-responsive nanoparticles that deliver drug payloads to endosomes of pain-sensing and transmitting neurons.