UC San Diego

Chronic pain affects billions and billions of people worldwide and its underlying mechanisms responsible are vast and poorly understood. Both neural and immune mechanisms play a role in the development and maintenance of chronic pain. Toll-like receptors (TLRs) are a family of receptors that play a key role in the innate immune system, many of which are associated with foreign bodies or genomic material derived from pathogens. Additionally, TLRs are also activated by endogenous cell components secondary to cell death, endocytosis, and inflammatory tissue damage. Although TLRs are widely known to play a role in the response to infectious processes, current work indicates the presence of endogenous TLRs in the nervous system, particularly on non-neuronal, glial cells. These non-neuronal, glial cells are mechanistically involved in regulating local system excitability secondary to high intensity afferent input and nerve injury. This organization suggests that TLRs may play a role in mediating spinal sensitization initiated by peripheral stimulation. I aim to characterize the role of spinal TLRs and define their contribution to the spinal processing of nociceptive information. Organizing hypothesis : Following nerve injury, the activation of TLRs contributes to spinal sensitization due to their direct activation of non- neuronal cells and the resulting release of central pain mediators. Additionally, TLRs and their signaling intermediaries, or adaptor proteins, determine the recovery pathway after initial insult. To investigate the above hypotheses, I will utilize both in vitro and in vivo models and will undertake experiments to address three primary aims : (1) Determine which TLRs present on primary astrocyte and microglial cells initiate glial activation, as assessed by cytokine and interferon release; (2) Determine the role of spinal TLRs in the facilitated pain state and the contribution of specific TLR adaptor proteins following acute pain; (3) Establish the role of TLR activation in the associated hyperalgesia produced by peripheral nerve injury, and assess glial activation and contribution of adaptor proteins to this hyperalgesic state. Taken together these studies will define the role of the several TLRs in regulating dorsal horn excitability leading to behaviorally defined changes in pain processing