Monday, March 13, 2017
4:00 PM - 5:00 PM
Where: Robert H Lurie Medical Research Center, Searle Seminar Room, 303 E. Superior, Chicago, IL 60611 map it
Audience: Faculty/Staff - Student - Public - Post Docs/Docs - Graduate Students
Category: Lectures & Meetings
The Department of Pharmacology invites you to a faculty speaker lecture presented by Daniela M. Menichella, M.D., Ph.D., Assistant Professor in the Department of Neurology at Northwestern University Feinberg School of Medicine.
Painful diabetic neuropathy (PDN) is one of the most common and intractable symptoms of diabetes, affecting 25% of diabetic patients. The hallmarks of PDN are neuropathic pain and small fiber degeneration, manifested by the loss of dorsal root ganglion (DRG) nociceptor axons. Neuropathic pain is associated with nociceptor hyper-excitability in the absence of physiologically appropriate stimuli. In states of neuropathic pain, DRG nociceptors become increasingly responsive to a variety of excitatory influences, including inflammatory cytokines. In particular, we have shown that stromal cell derived factor-1 (SDF-1) and its receptor CXCR4 are necessary for the generation of neuropathic pain in mouse models of PDN. However, the molecular mechanisms leading to the hyper-excitability of DRG nociceptors in PDN are unknown, as are the mechanisms leading to small fiber degeneration. This fundamental gap in our knowledge represents a critical barrier to progress in developing novel therapeutic approaches for PDN. The objective of this study is to identify the molecular cascade linking CXCR4/SDF-1 chemokine signaling to DRG nociceptor hyper-excitability, neuropathic pain, and small fiber degeneration in PDN. DRG nociceptors can be identified by a series of molecular markers, including expression of the sodium channel Nav1.8. Indeed, >90% of Nav1.8-expressing DRG neurons are nociceptors. Feeding mice a high fat diet (HFD) for several weeks induces glucose intolerance, obesity, and mechanical allodynia, a particular pain hypersensitivity associated with PDN. Using the HFD model combined with DREADD receptor technology, we have shown that reducing excitability of Nav1.8-expressing neurons prevents and reverse neuropathic pain, neuronal calcium overload, mitochondrial dysfunction, and small fiber degeneration. Furthermore, we have shown that CXCR4 receptors are necessary for neuropathic pain and small fiber degeneration in PDN. Taken together these data demonstrate that Nav1.8 nociceptor hyperexcitability in PDN is driven through the activation of CXCR4 receptors. Inhibition of hyperexcitability can prevent and reverse the development of PDN. Furthermore, these observations will advance our understanding as to how changes in excitability, calcium influx, and mitochondrial dysfunction in nociceptors contribute to neuropathic pain and small fiber degeneration in PDN, which is a critical barrier to progression for effective and disease modifying treatment for PDN.