| In the completion of these studies, we employ a well-established pain model, the chronic constriction injury (Bennett) model of mononeuropathy to study alterations in adrenergic neuronal functioning in the CNS during neuropathic pain. We examine alterations in levels of TNFalpha within various regions of the CNS, as well as changes in presynaptic sensitivity to TNFalpha and alterations in alpha2-adrenergic receptor sensitivity within the CNS during neuropathic pain. Furthermore, we investigate the requirement for elevations in levels of TNFalpha within the brain for the development of neuropathic pain.;Accumulation of TNFalpha is increased in a region of the brain containing the locus coeruleus, followed by an increase in the hippocampus, coincident with the development of hyperalgesia. Additionally, accumulation of mRNA specific for TNFalpha is increased during neuropathic pain in neurons within a region of the brain containing the locus coeruleus. Concurrently, alpha2-adrenergic receptor sensitivity, and TNFalpha-induced inhibition of norepinephrine (NE) release are increased, and stimulated NE release is decreased in hippocampal slices isolated from animals manifesting neuropathic pain, suggesting a cause and effect. Similarly, levels of TNFalpha in the thoraco-lumbar spinal cord are increased, and stimulated NE release from superfused lumbar spinal cord slices isolated from animals experiencing neuropathic pain is decreased. However, in contrast to that which occurs in the hippocampus, alpha2-adrenergic receptor inhibition of NE release does not change in the spinal cord during neuropathic pain. Additionally, inhibition of TNFalpha activity within the brain early in the development of neuropathic pain completely abolishes the hyperalgesic response characteristic of this model, while central administration of exogenous TNFalpha to control animals produces hyperalgesia similar to that observed following CCI. 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 alpha2-adrenergic autoreceptors and increased inhibition by TNFalpha culminate in decreased NE release in the brain. These neuroplastic changes provide a mechanism for the role of CNS-derived TNFalpha in the pathogenesis of persistent pain. |
