Exploring the Glial Mechanisms Underlying Central Neuropathic Pain in a Novel Rat Model of Spinal Cord Injury
Neuropathic pain is a debilitating condition that is usually intractable to treatment. Spinal cord injury (SCI) is the leading cause of central neuropathic pain (CNP), and patients often describe their pain as severe and intolerable. Although most of the focus in the pain literature has been on neurons, it is now well known that non-neuronal cells of the central nervous system called microglia and astrocytes (herein referred to as “glial cells” or “glia”) play a key role in the induction and maintenance of neuropathic pain. Glia are immune cells that are normally in a surveying/quiescent state, but upon activation by an inflammatory stimulus, they release a host of proinflammatory mediators that can sustain neuropathic pain for weeks, months, and even years. Interestingly, glia can also release anti-inflammatory mediators, making them ideal for therapeutic targeting. The glial mechanisms underlying CNP have not been fully explored and understood, and Chapter II is a set of studies undertaken to determine the involvement of glia in a novel rat model of thoracic-13/lumbar-1 (T13/L1) dorsal root avulsion SCI termed Spinal Neuropathic Avulsion Pain (SNAP). SNAP induced a robust, reliable, long-lasting below-level hind paw allodynia that was reversed by 3 different glial activation inhibitors. These studies confirmed that glia are involved in the mechanism underlying SNAP and that use of therapies that target glial cells could provide a better route for treating CNP. The studies in Chapter III determined that CNP could be attenuated by a single injection of an adenosine A2A receptor agonist for at least 6 weeks. This attenuation is due to a decrease in glial activation and proinflammatory cytokine expression, and at least in part dependent on the anti-inflammatory cytokine IL-10. The studies in Chapter IV detail a phenomenon in which administering opioids shortly after SNAP increases the magnitude of allodynia and potentiates the expression of proinflammatory mediators. This mechanism is at least in part dependent on toll-like receptor 4 and the proinflammatory cytokine IL-1β. The evidence from this dissertation suggests that glial cells are critically involved in the mechanisms underlying CNP, and that they can be manipulated to attenuate or potentiate CNP depending on their microenvironment and pattern of receptor activation.