Molecular-Genetic Mechs Underlying Effects of Anti-inflammatory/Analgesic Drugs

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Tissue injury initiates a cascade of proinflammatory mediators and hyperalgesic substances including prostaglandins, cytokines and chemokines. Interactions of cytokine and chemokine and activation of their signaling pathways contribute to the development of inflammation and inflammatory pain. Inflammation is also regulated by the synthesis and release of prostaglandins, bradykinin, nitric oxide (NO) and cell adhesion molecules that also activate pathways that contribute to the development of inflammation and inflammatory pain. For decades, non-steroidal anti-inflammatory drugs (NSAIDs) have been the mainstay of treatment for inflammatory disorders and inflammatory pain but the recognition of an inducible form of cyclooxygenase (COX) provided a rationale for developing selective COX-2 inhibitors to avoid the adverse gastrointestinal effects of COX-1 suppression by traditional NSAIDs. However, increasing evidence indicates that this model is too oversimplified to explain the observed differences in therapeutic and adverse effects of traditional NSAIDs and COX-2 inhibitors in clinical and experimental studies. New insights into the biological properties of proinflammatory mediators and anti-inflammatory/analgesic drugs suggest that they have more independent effects than their role in the amelioration of inflammatory pain. Our recent series of studies using a clinical model of tissue injury demonstrate that peripheral expression profiles of cytokines/chemokines are differently regulated at early and later time points in the development of inflammation. NSAIDs and selective COX-2 inhibitors show different regulatory effects on their gene expression and pathways. Using microarray and qRT-PCR gene expression analyses, we evaluated changes in gene expression profiles of cytokines/chemokines and their correlation with patient-reported pain intensity following tissue injury in a well characterized model of acute inflammatory pain. Pain intensity gradually increased postoperatively with local anesthetic offset. At the early phase of inflammation and inflammatory pain, tissue injury resulted in a significant up-regulation in the gene expression of IL-6, IL-8, CCL2, TNF-, CXCL1, CXCL2. The up-regulation of IL-6 gene expression was significantly correlated to the up-regulation of the gene expression of IL-8, CCL2, CXCL1 and CXCL2. Interestingly, the tissue injury-induced up-regulation of IL-6, IL-8 and CCL2 gene expression was positively correlated to pain intensity at this early time point, the onset of acute inflammatory pain. We further found that at this early time point, the kinin B1 receptor was up-regulated at the transcriptional level in response to kinin activation and was associated with the production of IL6, IL8 and CCL2 via the activation of TRPV1 receptors. One of our interesting findings is that the expression of phosphodiestrase type 4 (PDE4D) was significantly increased at this early time point following tissue injury. Selective and non-selective COX-inhibitors reduced the up-regulation of PDE4D, which may indicate a novel mechanism contributing to NSAIDs analgesic and anti-inflammatory effects. However, in the later phase of the development of inflammation and inflammatory pain, we found that tissue injury-induced up-regulation of IL8 was significantly correlated with the up-regulation of matrix metalloproteinase (MMP) pathways including MMP-1, MMP-3 and PLAT, which might represent a novel therapeutic target in the management of chronic inflammatory pain in clinical practice as MMP pathways have been implicated in regulating neurovascular permeability and demyelination in patients with symptomatic neuropathy. Recent studies have emphasized the important contribution of the inflammatory cytokines and chemokines to the development of peripheral neuropathic pain. Inflammatory cell infiltration and subsequent secretion of cytokines, chemokines, prostaglandins, bradykinin and nitric oxide play pivotal roles in the pain/hyperalgesia mechanisms of peripheral neuropathy caused by trauma, diabetes and chemotherapy. Our these findings provide evidence at the gene expression level of novel pathways involved in acute inflammatory pain in human that may help to identify the targets for intervention in patients with chronic pain. Future directions will focus on the symptoms biology of cancer treatment complications such as chemotherapy-induced peripheral neuropathic pain and evaluation of phophodiesterase and MMP inhibitors as potential novel therapeutic and neuroprotective strategies.