Decoding pain and opioid addiction. Transforming treatment.

The Scherrer Lab investigates how cells and molecules within neural circuits generate pain perception and pain-related suffering, as well as the pain-relieving and adverse effects of opioids, including tolerance, addiction, and respiratory depression.

Our research spans the entire pain pathway—from sensory neurons in peripheral tissues and spinal circuits that process signals from the body to brain networks that construct the sensory, emotional, and cognitive dimensions of pain. We also investigate how opioids act throughout these circuits.

By identifying receptors and signaling mechanisms within specific cell types, we aim to develop small-molecule drugs that can relieve pain without engaging the pathways responsible for addiction and other serious adverse effects. In parallel, we investigate how pain-control circuits can be recruited using noninvasive neuromodulation devices.

We also seek to understand how cognitive factors such as expectation and cognitive behavioral therapies engage the brain’s own pain-relief systems. By translating discoveries across molecules, cells, circuits, and behavior, our goal is to create safer, more effective, and more personalized treatments for pain and opioid addiction.

FROM THE BODY

Pain signaling begins with specialized sensory neurons whose endings innervate the skin, joints, bones, muscles, and internal organs. These neurons detect mechanical, thermal, and chemical stimuli that may threaten the body. In this image, sensory nerve endings shown in magenta surround mechanosensory Merkel cells shown in green. We investigate how peripheral sensory systems distinguish innocuous touch from signals that can initiate pain.

SENSORY NEURONS

Signals detected throughout the body travel along sensory neurons whose cell bodies are located in dorsal root ganglia beside the spinal cord. Related neurons in the trigeminal ganglia innervate the head and face. This cross-section reveals molecularly distinct populations of sensory neurons specialized to detect touch, temperature, tissue injury, and other stimuli. We characterize these populations to understand how different sensory signals enter the pain pathway.

SPINAL PAIN CIRCUITS

The spinal cord is the first central processing center for sensory information. Here, sensory inputs from muscles, shown in red, enter the dorsal spinal cord. PKCγ-expressing neurons, shown in blue, help process and integrate information arriving from the body, while NK1R-expressing projection neurons, shown in green, relay selected pain-related signals toward the brain. We study how these spinal circuits amplify, suppress, or transform sensory information.

THE PAIN EXPERIENCE

In the brain, sensory information is transformed into the multidimensional experience of pain—including its location and intensity, its unpleasant emotional quality, and pain-related suffering. We discovered an amygdala neural ensemble that gives pain its unpleasantness and identified a cingulate cortex–pons–cerebellum circuit through which positive expectations can produce pain relief. These studies reveal that pain is not simply received by the brain: it is actively constructed and controlled.

MAPPING THE BRAIN’S RESPONSE TO OPIOIDS

This image visualizes individual neurons activated by morphine across the cerebral cortex. Morphine-responsive neurons are labeled in red, while SATB2 co-labeling identifies excitatory cortical neurons. By mapping the specific cells recruited by opioids, we seek to understand how opioids change brain activity and how repeated exposure can contribute to dependence and addiction.