Date of Completion
Pain; thermal hyperalgesia; mechanical hypersensitivity; CD63; Ongoing Pain; Matrix metalloproteinase; Conditioned place preference
Kyle Baumbauer Ph.D.
Stephen Crocker Ph.D.
Royce Mohan Ph.D.
Erin Young Ph.D.
Field of Study
Doctor of Philosophy
Persistent pain is a significant clinical problem that affects millions of people worldwide. The severity of acute pain and inflammatory signaling during tissue damage can predispose an individual to develop pain that persists past the normal healing time. In my thesis work, I focused on how molecules involved in the regulation of inflammation and normal wound healing contribute to the progression of pain.
During tissue damage and inflammation, Tissue inhibitor of metalloproteinase-1 (TIMP-1) is upregulated to maintain tissue homeostasis as well as promote normal inflammatory signaling. Recent evidence suggests that TIMP-1 may reduce the development of nerve-injury induced pain, however how TIMP-1 contributes to pain processing required further investigation. Although primarily known as an MMP inhibitor, TIMP-1 has dual functions that can both disrupt ECM proteolysis as well as bind cell-surface receptors to mediate intracellular signaling pathways. In this proposed thesis work, in light of these dual functions, I examined the role of TIMP-1 in the development of hypersensitivity using a model of cutaneous inflammation. Our preliminary data suggested that inflammation induces TIMP-1 expression in inflamed skin in a time course that parallels the development of acute inflammatory pain, and that mice lacking TIMP-1 (T1KO mice) develop rapid onset and heightened sensitivity following inflammation.
In my thesis work, I determined that TIMP-1 plays a significant role in regulating the progression of inflammatory pain. As described in chapter 3, the induction of TIMP-1 during the onset of inflammation is important for reducing peripheral hypersensitivity that may be important for the development of pathological pain-like behaviors. In addition, I discovered that the absence of TIMP-1 resulted in rapid-onset hypersensitivity that persisted for long periods of time in tissues proximal and distal (e.g., mirror image pain) to the site of inflammation. Importantly, administration of full length recombinant TIMP-1, its MMP-inhibiting N-terminal, or its receptor binding C-terminal all attenuate inflammatory hypersensitivity.
Results from the proposed work demonstrate that during tissue damage, TIMP-1 signaling affects the normal progression of pain following inflammation through MMP-dependent and MMP-independent mechanisms.
Knight, Brittany, "Role of Tissue Inhibitor of Matrix Metalloproteinase-1 in the Development of Hypersensitivity Using an Animal Model of Cutaneous Inflammation" (2019). Doctoral Dissertations. 2324.