Brain-derived TNFα: Involvement in neuroplastic changes implicated in the conscious perception of persistent pain

The pleiotropic cytokine tumor necrosis factor-alpha (TNFα) is implicated in the development of persistent pain through its actions in the periphery and in the central nervous system (CNS). Activation of the α₂-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 TNFα and the α₂-adrenergic autoreceptor in the pathogenesis of neuropathic pain. Accumulation of TNFα 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 TNFα in the hippocampus at day 8 post-ligature placement, coincident with hyperalgesia. Levels of TNFα in the thoraco-lumbar spinal cord are also increased at day 8 post-ligature placement. Concurrently, α₂-adrenergic receptor and TNFα-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, α₂-adrenergic receptor inhibition of NE release is not changed. These results indicate an important role that TNFα 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 α₂-adrenergic autoreceptors and increased presynaptic sensitivity to TNFα, culminate in decreased NE release in the CNS. These neuroplastic changes provide a mechanism for the role of CNS-derived TNFα in the pathogenesis of persistent pain.