Previously published work by our lab evaluating injury-induced changes in sensory neuron protein expression identified substantially increased levels of the neurosecretory protein VGF (non-acronymic), a neuropeptide precursor. To further characterize the functional role of VGF-derived peptides in sensory neuron signaling and in the development of pain-relevant behavior, we utilized animal models, behavior analyses, and complementary morphologic and molecular techniques to pursue two approaches: using adeno-associated virus (AAV) vectors to modulate VGF expression in primary afferent neurons, and exploring whether VGF up-regulation is limited to somatic pain. From this work, we learned intrasciatic administration of AAV5 vectors yields inefficient and variable transduction of sensory and motor neurons, reminiscent of the AAV8 serotype. Intrathecal administration of AAV5-VGF resulted in successful transduction of the choroid plexus but poor expression in dorsal root ganglion (DRG) sensory neurons. Unexpected DRG sensory neuron degeneration was observed following highly-efficient transduction of AAV9, warranting caution in future experiments utilizing this vector serotype. Antibiotic-induced visceral hypersensitivity was associated with up-regulation of VGF and other nociceptive neuropeptides in sensory neurons of the sixth lumbar DRG. However, contrary to expectations, referred cutaneous allodynia associated with antibiotic-induced visceral hypersensitivity was not readily detected using a non-invasive mechanical stimulation assay. Collectively, these findings encourage a re-evaluation of the tools employed to modulate VGF expression in primary afferent neurons in vivo, support the investigation of this novel signaling system beyond models of nerve injury, and are presented such that they can be used as an aid in the design of future work.
University of Minnesota Ph.D. dissertation. July 2015. Major: Comparative and Molecular Biosciences. Advisors: Lucy Vulchanova, Alvin Beitz. 1 computer file (PDF); x, 192 pages.
Pain-relevant behavior associated with VGF expression in primary afferent neurons.
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