Adenylyl Cyclase Signaling in Persistent Pain

This research project focuses on advancing understanding of molecular signaling pathways that contribute to chronic, persistent pain. Persistent pain is a major clinical challenge with significant impacts on quality of life, function, and health care utilization. This project centers on the adenylyl cyclase (AC) family of enzymes, which produce cyclic AMP (cAMP) in response to G protein–coupled receptor signaling and thereby regulate diverse cellular processes. By interrogating how dysregulation of AC signaling contributes to the transition from acute to persistent pain, the study aims to identify mechanistic drivers of long-lasting nociceptive sensitization and to reveal targets that could be modulated to restore normal signaling and reduce pathological pain. The research emphasizes a translational perspective: elucidating fundamental mechanisms of AC pathway dysfunction in relevant pain models and linking those mechanisms to measurable changes in neuronal and non-neuronal cell function that underlie persistent pain states. The project outlines efforts to map expression patterns of AC isoforms in tissues and cell types implicated in pain processing, characterize downstream cAMP-mediated signaling cascades, and determine how alterations in these pathways affect neuronal excitability, synaptic plasticity, and neuroimmune interactions.

By connecting molecular signaling events to alterations in sensory neuron function and spinal cord circuitry, the work seeks to bridge basic molecular insights with physiological and behavioral manifestations of chronic pain. A core element of the project is its focus on specificity: different AC isoforms and regulatory inputs can produce distinct spatial and temporal patterns of cAMP signaling. The study therefore considers isoform-specific roles and context-dependent regulation, aiming to distinguish adaptive signaling that supports normal nociceptive processing from maladaptive signaling that perpetuates pain. This nuanced view supports identification of therapeutic strategies that target pathological signaling while preserving normal physiologic functions.

Expected outcomes include a refined model of how AC signaling contributes to the development and maintenance of persistent pain, identification of candidate molecular targets within the AC–cAMP signaling axis, and generation of data to support downstream translational work. Such translational work could include screening for small molecules or biologics that modulate specific AC isoforms or their regulatory partners, validation of target engagement in preclinical models, and development of biomarkers that reflect dysregulated AC signaling in chronic pain patients. Beyond direct therapeutic implications, the project is positioned to enhance understanding of pain biology more broadly, informing research on comorbidities and intercellular signaling networks that influence pain chronification. By advancing mechanistic knowledge and highlighting actionable targets, Adenylyl Cyclase Signaling in Persistent Pain aims to contribute to improved strategies for preventing and treating persistent pain, reducing suffering and improving function for individuals affected by chronic pain disorders.