Brain-derived TNF alpha: involvement in neuroplastic changes implicated inthe conscious perception of persistent pain

The pleiotropic cytokine tumor necrosis factor-alpha (TNF alpha) is implica ted in the development of persistent pain through its actions in the periph ery and in the central nervous system (CNS). Activation of the alpha(2)-adr energic receptor is associated with modulation of pain, possibly through it s autoregulatory effect on norepinephrine (NE) release in the CNS. The pres ent study employs a chronic constriction nerve injury (CCI) pain model to d emonstrate the interactive role of presynaptic sensitivity to TNF alpha and the alpha(2)-adrenergic autoreceptor in the pathogenesis of neuropathic pa in. Accumulation of TNF alpha is increased initially in a region of the bra in containing the locus coeruleus (LC) at day 4 post-ligature placement, fo llowed by an increase in TNF alpha in the hippocampus at day 8 post-ligatur e placement, coincident with hyperalgesia. Levels of TNF alpha in the thora co-lumbar spinal cord are also increased at day 8 post-ligature placement. Concurrently, alpha(2)-adrenergic receptor and TNF alpha-induced inhibition of NE release are increased, and stimulated NE release is decreased in sup erfused hippocampal slices isolated at day 8 post-ligature placement. Stimu lated NE release is also decreased in spinal cord slices (lumbar region) fr om 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 TNF alpha plays in a drenergic neuroplastic changes in a region of the brain that, among its man y functions, appears to be a crucial link in the conscious perception of pa in. We predict that neuroplastic changes, involving increased functional re sponses of alpha(2)-adrenergic autoreceptors and increased presynaptic sens itivity to TNF alpha, culminate in decreased NE release in the CNS. These n europlastic changes provide a mechanism for the role of CNS-derived TNF alp ha in the pathogenesis of persistent pain. (C) 2000 Elsevier Science B.V. A ll rights reserved.