Neurotrophic factor signaling can modulate the structural and functional properties of sensory neurons. Small diameter, sensory neurons can be divided into two subpopulations based on the expression of neurotrophic factor receptors. Half express the nerve growth factor (NGF) receptor TrkA and half express the receptor tyrosine kinase Ret, which is the signaling receptor for neurotrophic factors belonging to the GDNF Family Ligands (GFLs). The specific contribution that these distinct populations of nociceptors make to pain transmission is unclear and has recently been a subject of considerable interest. The TrkA population of nociceptors has been studied extensively and much is known about the effects of NGF/TrkA signaling on nociception and of the mechanisms by which NGF/TrkA signaling modulates nociception. Much less is known about the more recently discovered GFLs and the mechanisms by which GFL/Ret signaling modulates nociception. Recent studies indicate that GFL/Ret signaling modulates nociception in the context of tissue or nerve injury and suggest that manipulation of Ret signaling could be an effective treatment for inflammation- or nerve injury-induced pain. However, the molecular mechanisms by which GFL/Ret signaling modulates nociception are largely unknown. A detailed understanding of these mechanisms is critical in order to effectively evaluate the therapeutic potential of manipulation of Ret signaling. The goal of our studies is to identify the role of GFL/Ret signaling in diverse models of sensory dysfunction and to determine the molecular mechanisms by which GFL/Ret signaling modulates nociception. Using a diverse approach that combines the power of mouse genetics with behavioral and physiological analyses we are investigating the signaling pathways and molecular effectors that underlie GFL/Ret-dependent modulation of nociception. We have created a novel set of mice in which specific aspects of Ret signaling are abrogated in sensory neurons by mutation of individual Ret tyrosine (Y) residues. These mice will allow us to identify Ret-activated signaling pathways that mediate GFL-induced analgesia and GFL-induced hyperalgesia. We are using calcium imaging and patch clamp electrophysiology to identify molecular effectors of GFL/Ret signaling. Identifying the signaling pathways and molecular effectors that mediate the effects of GFL/Ret signaling on nociception will provide insight into poorly understood mechanisms of pain and analgesia and has the potential to improve pain therapy.