Novel Polymeric Delivery Systems for Targeting Chronic Pain and Inflammation

The consequences of sustaining a spinal cord injury (SCI) can be overwhelming and can impact many areas of one’s life. An injury to the spinal cord can have catastrophic consequences on physical movement, bladder function and other voluntary and involuntary functions. Furthermore, SCI often results in debilitating pain that becomes chronic, and can either be neuropathic or nociceptive. Neuropathic pain arises from damage or dysfunction of the nervous system, affecting both the peripheral and central pathways. Neuropathic pain typically develops months or years after SCI and is often localized below the level of injury, though above-level pain can also occur.It is also aided with two sensory conditions – allodynia and hyperalgesia. Allodynia can be described as the pain sensation to a stimulus that does not generally induce pain, whereas hyperalgesia is the abnormally heightened sensitivity to pain. This increased discomfort caused by chronic pain can prevail for approximately 20% of a person’s lifespan. The development and maintenance of this chronic pain has been attributed to the hyper-excitability of the dorsal root ganglion (DRG) neurons. In turn, this sensitization of the DRG neurons can be manipulated with regulation of inflammatory cytokines, neuronal plasticity and ion channels transmissions. Along with the nervous system, the immune system plays an equally important role in regulating chronic pain and inflammation. Many cells of the immune system – toll-like receptors (TLRs), glia cells, microglia, macrophages, amongst others, orchestrate a cascade of cytokine and enzymatic responses in opposition to adverse environmental conditions. Neutrophils are the first immune cells to respond to injury, followed by macrophages, which play a key role in inflammation and healing. Macrophages exhibit remarkable plasticity, adapting their function in response to local environmental cues such as cytokines and tissue signals. In simple terms, macrophages can be categorized into inflammatory macrophages (M1-m) and anti- inflammatory macrophages (M2-m). At the site of injury, M1-m trigger an inflammatory response by releasing inflammatory cytokines. M2 macrophages contribute to tissue repair and resolution of inflammation by releasing anti-inflammatory cytokines and growth factors. The immune system regulates the resolution of inflammation through mechanisms such as regulatory T cells (Tregs) and anti-inflammatory cytokines. However, if inflammatory signals persist due to unresolved tissue damage or dysregulated immune responses, inflammation can become chronic, contributing to conditions like neuropathic pain.