Opioid receptors are expressed by small diameter nociceptive afferent fibers. Augmenting their expression by viral transduction may enhance the power of opioid agonists to inhibit the neurotransmission of pain signals to secondary spinal cord neurons. The adeno-associated virus (AAV) serotype has been shown to be useful for transduction of neurons in cortex, brainstem, and cerebellum. Its utility for transduction of neurons in the spinal cord and dorsal root ganglia (DRG) has also been explored with limited success due to meningeal barrier limitations. Our application of a hyperosmotic agent as a pre-treatment has resulted in significant gene transfer to the spinal cord and dorsal root ganglion neurons. The proposed research will assess the utility of delivery of AAV- vector by lumbar puncture as a useful tool for basic scientific study of chronic pain as well as a potential therapeutic delivery option. The primary objectives of the project are: 1) Validate efficacy of intrathecally administered AAV5 for delivery of target genes to the spinal cord and DRG neurons anatomically and neurochemically. 2) Validate antinociceptive functionality of genes transferred by intrathecal delivery of AAV5 vector to spinal cord and DRG neurons. The proposed fellowship, focused on neuropathic pain, will proceed in context with parallel studies involving opioid tolerance and self-administration. Gene therapy using viral vectors may permanently alter the molecules produced by neurons. This project seeks to augment the availability of opioid receptors to prevent or correct maladaptive changes.
|Chabot-Doré, A-J; Schuster, D J; Stone, L S et al. (2015) Analgesic synergy between opioid and ?2 -adrenoceptors. Br J Pharmacol 172:388-402|
|Schuster, D J; Metcalf, M D; Kitto, K F et al. (2015) Ligand requirements for involvement of PKC? in synergistic analgesic interactions between spinal ? and ? opioid receptors. Br J Pharmacol 172:642-53|
|Schuster, Daniel J; Kitto, Kelley F; Overland, Aaron C et al. (2013) Protein kinase C? is required for spinal analgesic synergy between delta opioid and alpha-2A adrenergic receptor agonist pairs. J Neurosci 33:13538-46|
|Schuster, D J; Dykstra, J A; Riedl, M S et al. (2013) Visualization of spinal afferent innervation in the mouse colon by AAV8-mediated GFP expression. Neurogastroenterol Motil 25:e89-100|
|Vulchanova, Lucy; Schuster, Daniel J; Belur, Lalitha R et al. (2010) Differential adeno-associated virus mediated gene transfer to sensory neurons following intrathecal delivery by direct lumbar puncture. Mol Pain 6:31|