Date of Award

5-1-2014

Degree Name

Doctor of Philosophy

Department

Pharmacology

First Advisor

Premkumar, Louis

Abstract

Based on duration, pain is categorized as acute and chronic pain. Acute pain is a short-term phenomenon that resolves after the noxious stimulus is removed or the injury is healed. On the other hand, chronic pain is a long-lasting debilitating condition. In a substantial number of cases, acute pain converts to chronic pain after months or years of the initial injury or damage. The current pain models are designed to study either acute or chronic pain, but not the transition from acute to chronic pain. Also, currently available pain models do not permit a direct comparison of molecular changes occurring in each condition or during the transitory process. Despite decades of research, current treatments seek to alleviate but not resolve chronic pain. Previous studies have shown that prolonged inflammation is a critical factor for initiation and maintenance of chronic pain. On a different platform of research, regenerative medicine strategies have employed Extracellular Matrix (ECM) for wound healing. This goal is achieved over a complex myriad of processes, which mainly involve inhibition of long-term inflammation. Based on these, I hypothesize that neurochemical changes become persistent in chronic pain conditions and components in ECM prevent these changes. The current study addresses two main issues: 1) establishing a pain model that allows the study of transition of acute to chronic pain and 2) using ECM as a possible therapy against chronic pain conditions. In the first aim of the study, low-dose of CFA induced acute pain (a short-term thermal hyperalgesia) and a high-dose of CFA induced chronic pain (a long-term thermal hyperalgesia and mechanical allodynia). In low-dose CFA-treated group, RT-PCR analyses revealed a significant increase in mRNA levels of anti-inflammatory mediators (IL-10, IL-13 and TGF-beta) and a significant decrease in mRNA levels of pro-inflammatory mediators (IL-1beta, IL-6, MCP-1, MMP-9, MMP-12 and TNF-alpha) and these neurochemical changes corresponded with behavior. In high-dose CFA-treated group, chronic pain states corresponded with a significant elevation of mRNA levels of pro-inflammatory mediators, while there was a significant decrease in mRNA levels of anti-inflammatory mediators. These findings were validated with well-established models of acute pain (intraplantar capsaicin or carrageenan) and chronic pain (Chronic Constriction Injury; CCI and Streptozotocin-induced neuropathy). The changes observed in low-dose CFA-treated group were similar to those of capsaicin or carrageenan treatment, whereas changes in the high-dose CFA-treated group resembled to those of CCI and STZ-treatment. TRPV1, a nociceptive ion channel expression and function were significantly increased in both acute and chronic pain models. TRPV1 function in the DRG is more pronounced in acute pain, while there was a greater change in the spinal cord in chronic pain, suggesting a differential role of DRG and spinal cord in acute and chronic pain conditions. The role of TRPV1 was further explored by intrathecal administration of RTX, which attenuated only inflammatory thermal hyperalgesia. These results demonstrate that graded doses of CFA as a possible model to study the transition from acute to chronic pain. Monocyte Chemoattractant Protein (MCP-1) and Matrix Metalloproteinases (MMP-9 and MMP-12) are key molecules; the levels of which increase in acute pain conditions and facilitate the transition to chronic pain conditions. In fact, RTX is in clinical trials as a viable treatment option in treating terminal debilitating cancer pain conditions. In the second aim of the study, high-dose of CFA treatment and CCI were used to mimic chronic pain conditions. Significantly, unlike RTX treatment, intrathecal administration of ECM alleviated both inflammatory thermal hyperalgesia and mechanical allodynia. ECM treatment also reduced the intensity of TRPV1 staining in spinal dorsal horn which, was substantiated by a significant decrease in basal and TRPV1-mediated CGRP release in spinal cord samples. RT-PCR analysis of spinal cord and DRG samples revealed that ECM treatment significantly decreased mRNA levels of several pro-inflammatory cytokines. On the other hand, mRNA levels of anti-inflammatory mediators were significantly increased after ECM treatment in both DRG and spinal cord samples. ECM treatment also decreased intensity of OX-42 (a marker for activated microglia) staining in the spinal dorsal horn. Taken together, these data suggest that ECM treatment restores homeostasis by balancing the levels of pro-inflammatory and anti-inflammatory mediators, which leads to alleviation of chronic pain. Therefore, ECM or components in ECM may provide a novel treatment option for chronic pain.

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