Brain-derived tumor necrosis factor-alpha (TNF) mediates the antinociceptive effect of amitriptyline and modulates brain-body interactions during neuropathic pain
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The present study was designed to investigate the involvement of the cytokine tumor necrosis factor-α (TNF) in the brain in the antinociceptive mechanism of action of the antidepressant drug amitriptyline. Amitriptyline is one of the most commonly employed antidepressants in the clinical management of chronic neuropathic pain, however the mechanism of its action remains unknown. Previous studies from our laboratory have demonstrated a central role of elevations in brain-derived TNF levels in the pathogenesis of neuropathic pain. As an extension of these findings, in the present study, the involvement of this cytokine in the antinociceptive mechanism of amitriptyline was investigated. Furthermore, brain-body interactions during neuropathic pain were assessed by determining the effect of increased levels of TNF in the brain on the production and regulation of TNF production from peripheral macrophage was analyzed. Male, Sprague-Dawley rats underwent chronic constriction injury (CCI) to the sciatic nerve. Elevated levels of TNF in the brain so induced modify the α 2 -adrenergic regulation of TNF production from peripheral macrophage, from potentiation in control macrophage to inhibition in macrophage harvested from rats experiencing peak thermal hyperalgesia, a characteristic symptom of neuropathic pain. This transformation was mimicked by intracerebroventricular microinfusion of rat recombinant TNF alone in rats. Amitriptyline treatment alleviated or even prevented the development of thermal hyperalgesia, depending on the time of treatment initiation. This was coincident with inhibition of pain-induced increases in neuron-derived TNF in the brain. Past this therapeutic window, amitriptyline treatment was inefficaious in alleviating thermal hyperalgesia. Analysis of α 2 -adrenergic regulation of macrophage in these paradigms revealed an interesting correlation between alleviation of thermal hyperalgesia and occurrence of a transformation in α 2 -adrenergic regulation of TNF production from peripheral macrophage. In fact, this transformation is not evident in a paradigm where amitriptyline treatment was inefficaious. Collectively, these data demonstrate that a transformation in α 2 -adrenergic regulation of TNF production in the periphery is an essential feature associated with spontaneous dissipation or effective treatment of thermal hyperalgesia in the CCI model. The nature of α 2 -adrenergic regulation of TNF production in the periphery appears to be an important indicator of the interactive relationship between these two cellular components.