The pleiotropic cytokine tumor necrosis factor-alpha (TNFalpha) is implicated in the development of persistent pain through its actions in the periphery and in the central nervous system (CNS). Activation of the alpha(2)-adrenergic receptor is associated with modulation of pain, possibly through its autoregulatory effect on norepinephrine (NE) release in the CNS. The present study employs a chronic constriction nerve injury (CCI) pain model to demonstrate the interactive role of presynaptic sensitivity to TNFalpha and the alpha(2)-adrenergic autoreceptor in the pathogenesis of neuropathic pain. Accumulation of TNFalpha is increased initially in a region of the brain containing the locus coeruleus (LC) at day 4 post-ligature placement, followed by an increase in TNFalpha in the hippocampus at day 8 post-ligature placement, coincident with hyperalgesia. Levels of TNFalpha in the thoraco-lumbar spinal cord are also increased at day 8 post-ligature placement. Concurrently, alpha(2)-adrenergic receptor and TNFalpha-induced inhibition of NE release are increased, and stimulated NE release is decreased in superfused hippocampal slices isolated at day 8 post-ligature placement. Stimulated NE release is also decreased in spinal cord slices (lumbar region) from animals undergoing CCI, although in contrast to that which occurs in the hippocampus, alpha(2)-adrenergic receptor inhibition of NE release is not changed. These results indicate an important role that TNFalpha plays in adrenergic neuroplastic changes in a region of the brain that, among its many functions, appears to be a crucial link in the conscious perception of pain. We predict that neuroplastic changes, involving increased functional responses of alpha(2)-adrenergic autoreceptors and increased presynaptic sensitivity to TNFalpha, culminate in decreased NE release in the CNS. These neuroplastic changes provide a mechanism for the role of CNS-derived TNFalpha in the pathogenesis of persistent pain.