Glial cell involvement in pathological pain conditions, neuroimmune interactions in chronic inflammatory diseases of the central nervous system, spinal cord gene therapy, motor neuron degenerative diseases
Dr Milligan’s Research focuses on glial neurobiology in chronic neuropathic conditions such a pathological pain. In the clinic, existing pain treatments reduce pain by only ~25-40% in less than half of the 15 million patients suffering from chronic neuropathic pain in the US. This underscores the significance of developing new applications to identify cellular processes that not only include neurons, but also non-neurons in the central nervous system. Modern views of pain processing now include critical roles of glial cells. Following incoming pain signaling from damaged peripheral nerves, spinal cord cytokines, IL-1β & TNF-α, released from glia contribute to persistent pathological pain. Additionally, chemokines (chemo-tactic signaling factors that induce peripheral immune cell trafficking) interact with cytokines to further mediate pathological glial-neuronal signaling. Thus, a key focus of this lab is examining the neuroimmune mechanisms that create chronic neuropathic pain. In understanding one potential cause for when good pain turns bad, we can discover novel therapeutics to treat pain in people. One approach the lab has been focused on is to control the actions of proinflammatory cytokines by applying the anti-inflammatory cytokine, interleukin-10 (IL-10), which potently inhibits proinflammatory cytokine pain-related actions. This lab explores IL-10 gene therapy using non-viral vectors delivered to the spinal cord to control glial cell-mediated neuropathic pain.
Ongoing research examines several immune-related events, including chemotaxis, mitosis, and phagocytosis that may play critical roles for optimal IL-10 gene transfer in the central nervous system. Additional ongoing research explores drug-delivery devices thought to further optimize gene transfer for pain therapy. One promising approach is the use of FDA-approved synthetic co-polymers that improve IL-10 gene delivery to the spinal cord. In addition to co-polymers, we have begun to examine other drug delivery methods. Our recent endeavors include exploring entirely novel gene delivery devices that may be additionally promising for future drug development. These studies are conducted in collaboration with Dr. Brinker, Professor of Chemical and Nuclear Engineering here at UNM, who has designed nanoparticle silica cores with definable mesoporosity. Thus, we are examining these co-polymers and nanoparticle silica transgene delivery vehicles in the context of neuroimmune interactions to ultimately achieve enduring therapeutic transgene expression in the spinal cord.
Additional research in this lab is exploring the effects of cannabinoid compounds that are thought to selectively bind cannabinoid type 2 receptors (CB2) expressed on glial cells in the spinal cord to control chronic inflammatory spinal cord diseases including neuropathic pain. Highly selective CB2 agonists may result in anti-inflammatory activity in addition to other protective effects. We apply a variety of methods to explore the role of CB2 activation for chronic pain control that includes protein assays, and fluorescent and confocal microscopy following immunohistochemical procedures.
Lastly, in collaboration with the Department of Anesthesiology & Critical Care Medicine with Dr. Martin, and with the KUSAIR Imaging facility in the College of Pharmacy with Dr. Norenberg, we are refining the role that peripheral immune cells may play in mediating pathological neuronal signaling and are identifying novel therapeutic targets to control clinical pain.