Novel Neuroimmune Interactions in the Context of Neuropathic Pain and Anti-inflammatory Modulation with Transforming Growth Factor-[beta]1

Download or read book Novel Neuroimmune Interactions in the Context of Neuropathic Pain and Anti-inflammatory Modulation with Transforming Growth Factor-[beta]1 written by Estefania Echeverry Castano and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Neuropathic pain is a debilitating problem affecting millions of people worldwide. This condition affects the quality of life and bears a substantial economic burden on society. Current drug treatments are often inadequate to treat this type of chronic pain, as they provide limited relief and are often accompanied with many undesired and difficult to manage side effects. It is imperative thus, to find new treatments that target alternative mechanisms from the currently approved drugs.The pathogenesis of neuropathic pain is very complex and involves structural, physiological and pharmacological changes throughout the neural axis (from the site of peripheral nerve injury to the spinal cord/brain). While a neuron-centric view has dominated the literature for decades and the way we approach neuropathic pain treatment, recent work has uncovered extensive neuroimmune interactions as substrates of this condition. Interactions between the immune and nervous systems occur at multiple levels, where different types of immune/glial cells and immune-derived substances are implicated in various stages of the pathogenesis. The four experimental chapters contained in this dissertation are in line with this recent recognition of the importance of neuroimmune mechanisms in neuropathic pain. In the work presented here, we sought to unravel novel neuroinflammatory mechanisms driving the aberrant pain condition in both the spinal cord and the peripheral nerve as well as to investigate the role of a potent anti-inflammatory cytokine, TGF-[beta]1, as a potential modulator of these mechanisms. Several important mechanisms have been observed: A) Modulation of the central and peripheral inflammatory reaction with TGF-[beta]1 significantly delays and attenuates mechanical allodynia and thermal hyperalgesia via immunosuppressive actions on glial cells (Chapter 2) and macrophages (Chapter 3). In the spinal cord TGF-[beta]1 inhibits microglial proliferation, astrocytic activation and release of pro-inflammatory cytokines and exerts neuroprotective effects resulting in a decrease in the production of MCP-1. At the site of the injury, exposure to TGF-[beta]1 reduces the number of macrophages, which release pro-inflammatory mediators, and modulates different populations of T-cells. B) In chapter 4 we demonstrate that sciatic nerve injury-induced neuropathic pain is associated with an increased permeability of the blood spinal cord barrier (BSCB). We observed that the spinal inflammatory reaction triggered by nerve injury is a key player in modulating this BSCB impairment. We identified MCP-1 as an endogenous trigger of BSCB leakage, which could be reversed using anti-inflammatory molecules TGF-[beta]1 and IL-10. C) Selective depletion of microglia with MAC-1-saporin results in impairment of mechanical and thermal hypersensitivities at both acute and chronic stages following nerve injury suggesting an important and persistent contribution of microglia in the pathogenesis of neuropathic pain. These results expand our understanding of the neuro-inflammatory mechanisms of neuropathic pain as well as propose that immunosuppression or blockade of the reciprocal signalling pathways between neuronal and non-neuronal cells offer new opportunities for disease modification and more successful management of pain. " --