Antinociception mediated by alpha(2)-adrenergic activation involves increasing tumor necrosis factor alpha (TNFalpha) expression and restoring TNFalpha and alpha(2)-adrenergic inhibition of norepinephrine release.

The central component that establishes chronic pain from peripheral nerve injury is associated with increased tumor necrosis factor-alpha (TNFalpha) production in the brain. This study examined TNFalpha 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 TNFalpha 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 TNFalpha mRNA accumulation in these brain regions. In contrast, during hyperalgesia, alpha(2)-adrenergic activation enhances TNFalpha mRNA accumulation. Whether this enhanced TNFalpha 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 TNFalpha regulation of NE release. While inhibition of NE release by TNFalpha is maximal during peak hyperalgesia, it subsequently transforms to facilitate NE release. In addition, alpha(2)-adrenergic receptor activation with clonidine (0.2mg/kg, i.p.) in CCI rats experiencing hyperalgesia restores TNFalpha and alpha(2)-adrenergic inhibition of NE release. While TNFalpha directs the development of hyperalgesia, it also directs its resolution. Transformed sensitivity to alpha(2)-adrenergic agonists during hyperalgesia demonstrates a mechanism for therapy.