Ketamine-induced Antinociception is Associated with Perception of Pain and Central TNFα Levels
LaMacchia, Zach Michael
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Current research shows that cytokines are major regulators of neuropathic pain. Specifically, tumor necrosis factor-alpha (TNFα) plays a major role in neuropathic pain, as it acts on different glial cells such as oligodendrocytes and microglia, as well as directly on neurons. After an injury, TNFα is released by inflammatory cells as well as from damaged neurons and induces the production of other cytokines (i.e., IL-1 and IL-6) by macrophages. These cytokines enhance sensory neuron firing, which is involved in the pathogenesis of neuropathic pain. During neuropathic pain, elevated levels of TNFα have also been identified in the brain, specifically in the hippocampus, a region associated with learning, memory formation, perception and cognitive function. Therefore, downregulation of TNFα in the hippocampus may eliminate the affective component of pain, or pain perception. Clinically, tricyclic antidepressants are currently used to treat patients with neuropathic pain, but they carry unwanted side effects, so there is a need to explore other drug options. Previous studies have shown that sub-anesthetic doses of ketamine have lowered TNFα systemically and in the hippocampus. The mechanism of how ketamine interferes with the neuroinflammatory cascade, and whether or not it has an effect on the deeper learning process of the perception of pain, is not fully understood. In this study, we induce neuropathic pain using the chronic constriction injury (CCI) protocol and monitor the animal’s sensitivity to hot and cold stimuli. Thermal measurements will reveal any antinociceptive effects of the experimental drugs on the sensory component of pain. To test the cognitive component of antinociception (or perception of pain), we used the conditioned placed preference (CPP) paradigm. Animals that formed a preference, or CPP, for the drug paired chamber indicated that the drug had an analgesic effect. Central and peripheral TNFα levels were measured showing that ketamine decreased the expression of this cytokine. Therefore, ketamine-induced decrease in TNFα centrally and peripherally appears to be associated with alleviation of cognitive and sensory components of pain.