Asunto(s)

RESUMEN

The pleiotropic cytokine tumor necrosis factor-alpha (TNF) and alpha(2)-adrenergic receptor activation regulate norepinephrine (NE) release from neurons in the central nervous system. The present study substantiates the role of TNF as a neuromodulator and demonstrates a reciprocally permissive relationship between the biological effects of TNF and alpha(2)-adrenergic receptor activation as a mechanism of action of antidepressant drugs. Immunohistochemical analysis and in situ hybridization reveal that administration of the antidepressant drug desipramine decreases the accumulation of constitutively expressed TNF mRNA in neurons of the rat brain. Superfusion and electrical field stimulation were applied to a series of rat hippocampal brain slices to study the regulation of [(3)H]NE release. Superfusion of hippocampal slices obtained from rats chronically administered the antidepressant drug zimelidine demonstrates that TNF-mediated inhibition of [(3)H]NE release is transformed, such that [(3)H]NE release is potentiated in the presence of TNF, an effect that occurs in association with alpha(2)-adrenergic receptor activation. However, chronic zimelidine administration does not alter stimulation-evoked [(3)H]NE release, whereas chronic desipramine administration increases stimulation-evoked [(3)H]NE release and concomitantly decreases alpha(2)-adrenergic autoreceptor sensitivity. Collectively, these data support the hypothesis that chronic antidepressant drug administration alters alpha(2)-adrenergic receptor-dependent regulation of NE release. Additionally, these data demonstrate that administration of dissimilar antidepressant drugs similarly transform alpha(2)-adrenergic autoreceptors that are functionally associated with the neuromodulatory effects of TNF, suggesting a possible mechanism of action of antidepressant drugs.

Asunto(s)

RESUMEN

A reciprocally permissive interaction occurs between cellular responses elicited by the pleiotropic cytokine tumor necrosis factor-alpha (TNF) and alpha(2)-adrenergic receptor activation, such that each may adapt in response to modifications in the other's effects. Changes in presynaptic adrenergic sensitivity as well as neuronal sensitivity to TNF have been implicated in the mechanism of action of antidepressant drugs. The present study examines the influence of alpha(2)-adrenergic receptor activation on levels of TNF in regions of the brain associated with adrenergic function and the expression of mood. Additionally, the role of TNF as a neuromodulator is demonstrated by in vivo microinfusion of rrTNF proximal to the hippocampus. Administration to rats of an alpha(2)-adrenergic receptor agonist (clonidine) decreases levels of TNF in homogenates of rat locus coeruleus and hippocampus within 7.5 min. Chronic (14 days) administration of the antidepressant drugs desipramine or zimelidine transforms alpha(2)-adrenergic receptor-dependent decreases in TNF levels to increases in levels of TNF in the locus coeruleus. This transformation to an increase in total levels of TNF also occurs, although transiently, in the hippocampus following acute (1 day) antidepressant drug administration. The effect of TNF on presynaptic alpha(2)-adrenergic sensitivity was also investigated. Field stimulation of hippocampal slices from rats microinfused with rrTNF proximal to the hippocampus for 14 days demonstrates a decrease in fractional release of [3H]NE and an increase in alpha(2)-adrenergic autoreceptor sensitivity. These data demonstrate a mutual dependence between alpha(2)-adrenergic receptor activation and levels of TNF in the central nervous system that would culminate in an increase in neurotransmitter release following antidepressant drug administration.

Asunto(s)

RESUMEN

Neuropathic pain is a chronic pain state that develops a central component following acute nerve injury. However, the pathogenic mechanisms involved in the expression of this central component are not completely understood. We have investigated the role of brain-associated TNF in the evolution of hyperalgesia in the chronic constriction injury (CCI) model of neuropathic pain. Thermal nociceptive threshold has been assessed in rats (male, Sprague-Dawley) that have undergone loose, chromic gut ligature placement around the sciatic nerve. Total levels of TNF in regions of the brain, spinal cord and plasma have been assayed (WEHI-13VAR bioassay). Bioactive TNF levels are elevated in the hippocampus. During the period of injury, hippocampal noradrenergic neurotransmission demonstrates a decrease in stimulated norepinephrine (NE) release, concomitant with elevated hippocampal TNF levels. Continuous intracerebroventricular (i.c.v.) microinfusion of TNF-antibodies (Abs) starting at four days, but not six days, following ligature placement completely abolishes the hyperalgesic response characteristic of this model, as assessed by the 58 degrees C hot-plate test. Antibody infusion does not decrease spinal cord or plasma levels of TNF. Continuous i.c.v. microinfusion of rrTNF alpha exacerbates the hyperalgesic response by ligatured animals, and induces a hyperalgesic response in animals not receiving ligatures. Likewise, field-stimulated hippocampal adrenergic neurotransmission is decreased upon continuous i.c.v. microinfusion of TNF. These results indicate an important role of brain-derived TNF, both in the pathology of neuropathic pain, as well as in fundamental pain perception.

Asunto(s)