title: Sustained relief of neuropathic pain by AAV-targeted expression of CBD3 peptide in rat dorsal root ganglion.
abstract: The Ca(2+) channel-binding domain 3 (CBD3) peptide, derived from the collapsin response mediator protein 2 (CRMP-2), is a recently discovered voltage-gated Ca(2+) channel (VGCC) blocker with a preference for CaV2.2. Rodent administration of CBD3 conjugated to cell penetrating motif TAT (TAT-CBD3) has been shown to reduce pain behavior in inflammatory and neuropathic pain models. However, TAT-CBD3 analgesia has limitations, including short half-life, lack of cellular specificity and undesired potential off-site effects. We hypothesized that these issues could be addressed by expressing CBD3 encoded by high-expression vectors in primary sensory neurons. We constructed an adeno-associated viral (AAV) vector expressing recombinant fluorescent CBD3 peptide and injected it into lumbar dorsal root ganglia (DRGs) of rats before spared nerve injury (SNI). We show that selective expression of enhanced green fluorescent protein (EGFP)-CBD3 in lumbar 4 (L4) and L5 DRG neurons and their axonal projections results in effective attenuation of nerve injury-induced neuropathic pain in the SNI model. We conclude that AAV-encoded CBD3 delivered to peripheral sensory neurons through DRG injection may be a valuable approach for exploring the role of presynaptic VGCCs and long-term modulation of neurotransmission, and may also be considered for development as a gene therapy strategy to treat chronic neuropathic pain.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: G
authors.initials: G
authors.lastname: Fischer
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: B
authors.initials: B
authors.lastname: Pan
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: D
authors.initials: D
authors.lastname: Vilceanu
authors.affiliation: 1] Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA [2] Department of Anesthesiology, Medical College of Wisconsin, Zablocki VA Medical Center, Milwaukee, WI, USA.
authors.forename: Q H
authors.initials: QH
authors.lastname: Hogan
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yu
mesh_terms: D000700:Analgesics; D000818:Animals; D052158:Aptamers, Peptide / Q000235:genetics / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000378:metabolism*; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008159:Lumbar Vertebrae; D008297:Male; D009419:Nerve Tissue Proteins / Q000737:chemistry; D009437:Neuralgia / Q000628:therapy*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000378:metabolism
chemical_list: D000700:Analgesics; D052158:Aptamers, Peptide; C000590315:CBD3 peptide; D020864:Calcium Channels, N-Type; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C095114:collapsin response mediator protein-2