Antinociception mediated by α2-adrenergic activation involves increasing tumor necrosis factor α (TNFα) expression and restoring TNFα and α2-adrenergic inhibition of norepinephrine release

The central component that establishes chronic pain from peripheral nerve injury is associated with increased tumor necrosis factor-alpha (TNF alpha) production in the brain. This study examined TNF alpha and its reciprocally permissive role with alpha(2)-adrenergic activation during peak and progressive decline of thermal hyperalgesia in sciatic nerve chronic constriction injury (CCI). Accumulation of TNF alpha mRNA (in situ hybridization) increases in the hippocampus and locus coeruleus during the onset of neuropathic pain and persists as hyperalgesia abates. Activation of alpha(2)-adrenergic receptors in control rats decreases TNF alpha mRNA accumulation in these brain regions. In contrast, during hyperalgesia, alpha(2)-adrenergic activation enhances TNF alpha mRNA accumulation. Whether this enhanced TNF alpha production is associated with changes in the regulation of norepinephrine (NE) release was tested. Hippocampal slices were electrically depolarized to evaluate alpha(2)-adrenergic and TNF alpha regulation of NE release. While inhibition of NE release by TNF alpha is maximal during peak hyperalgesia, it subsequently transforms to facilitate NE release. In addition, alpha(2)-adrenergic receptor activation with clonidine (0.2 mg/kg, i.p.) in CCI rats experiencing hyperalgesia restores TNF alpha and alpha(2)-adrenergic inhibition of NE release. While TNF alpha directs the development of hyperalgesia, it also directs its resolution. Transformed sensitivity to alpha(2)-adrenergic agonists during hyperalgesia demonstrates a mechanism for therapy. (c) 2006 Elsevier Ltd. All rights reserved.