The Sheahan Lab is especially interested in how neuropeptides and their receptors shape the nervous system’s responses to the environment. Neuropeptides are a class of signaling molecules that neurons use to communicate with surrounding cells. In contrast to fast-acting neurotransmitters, neuropeptides act on a much slower timescale and have the potential to influence neural circuits in nuanced ways. Several of our ongoing research projects investigate the different ways in which neuropeptides and their receptors can shape the sensations of itch and pain.
How do neuropeptides shape spinal circuits
for itch?
Chronic itch disorders are the primary reason for visits to dermatologists and have devastating effects on patient quality of life, yet our limited understanding of how itch stimuli are transmitted within the nervous system has left chronic itch poorly managed. One hallmark of chronic itch is the upregulation of excitatory neuropeptides (e.g., substance P and gastrin-releasing peptide) in the spinal cord dorsal horn. Importantly, evidence from our recent work and others indicates that these neuropeptides are necessary and sufficient for scratching. However, we do not yet know how these neuropeptides act at the circuit level to drive itch. One possibility is neuropeptides simply act in parallel with neurotransmitters (i.e. glutamate), thereby reinforcing synaptic circuits. Alternatively, since neuropeptides are not restricted to the synapse, neuropeptide signaling may diverge from neurotransmitter targets, thereby fundamentally reconfiguring neural circuits. Initial experiments in the Sheahan Lab will address this gap in knowledge by investigating neuropeptide signaling in acute and persistent itch.
Listen to Tayler discuss this project here:
Can we find non-addictive treatments for chronic pain?
We are in the middle of an opioid epidemic, with thousands of American’s dying from opioid overdoses each year. Prescription opioids are used as a first-line treatment for the >50 million chronic pain patients in the U.S., putting them at greater risk for developing an opioid use disorder. This highlights the pressing need for new, safe treatments for chronic pain. Existing prescription opioids (e.g., morphine and Oxycodone) primarily target the mu opioid receptor. These drugs provide powerful pain relief but simultaneously act in regions of the brain that drive addiction. Accumulating evidence in rodents indicates that other classes of opioids, such as those that act on the kappa opioid receptor (KOR), represent promising, non-addictive strategies for pain relief. Like mu opioids, kappa opioids provide pain relief, but instead result in loss of feelings of joy and pleasure. Our lab is working to determine the mechanisms of kappa opioid-induced analgesia within the spinal cord.
Approaches
To explore these questions, the lab uses of a broad range of experimental approaches. Currently, these include:
Animal behavior: Behavioral pharmacology, chemogenetics, and (soon) automated behavioral analysis pipelines to dissect the neural basis of animal behavior.
Cellular physiology: Calcium indicators, multiphoton imaging on ex vivo preparation, and in vivo fiber photometry to visualize how and which neurons respond to sensory input as well as how neuronal activity corresponds to behavior
Molecular approaches: Viral tracing, immunohistochemistry, and in situ hybridization to understand the anatomy of rodent tissues, and assess the translational relevance in human tissues
We take a hypothesis-driven approach to science such that we will expand our technical expertise to best test our hypotheses. For that reason, our experimental toolkit is always evolving!
Sheahan Lab 