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Pathophysiological and pharmacological concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in the cerebrospinal fluid (CSF) induce anorexia in normal rats. Obesity in humans and rodents is associated with increased TNF-alpha messenger RNA and protein levels in various cell types. This suggests that obese individuals may have differential regulation of cytokine production and dissimilar responsiveness to cytokines. In the present study, we investigated the effects of the intracerebroventricular (ICV) microinfusion of TNF-alpha (50, 100, and 500 ng/rat), IL-1 beta (1.0, 4.0, and 8.0 ng), and TNF-alpha (100 ng) plus IL-1 beta (1.0 ng) on obese (fa/fa) and lean (Fa/Fa) Zucker rats. The results show that: TNF-alpha and IL-1 beta, and the concomitant administration of TNF-alpha and IL-1 beta decreased the short-term (4 hours), nighttime (12 hours), and total daily food intakes in obese and lean rats; IL-1 beta was more potent relative to TNF-alpha; obese rats showed greater responsiveness to IL-1 beta: 8.0 ng IL-1 beta, for example, decreased the 12-hour food intake by 52% in obese and 22% in lean rats. On the other hand, obese and lean rats did not exhibit a significantly different responsiveness to the anorexia induced by 50, 100, or 500 ng TNF-alpha at the 4-hour period; and the concomitant ICV administration of TNF-alpha and IL-1 beta induced anorexia with additive (4-hour period) or synergistic (12-hour and 24-hour periods) effects in obese rats. The effect of TNF-alpha plus IL-1 beta in lean rats was greater than additive for the 12-hour and 24-hour periods. The difference in suppression of total daily food intake by TNF-alpha plus IL-1 beta in obese (-43%) versus lean (-23%) rats was significantly different (p < 0.01). The results show that obese (fa/fa) and lean (Fa/Fa) Zucker rats have differential responsiveness to the ICV microinfusion of two different classes of cytokines.

Interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α) induce acute anorexia by direct action in the central nervous system (CNS) at estimated pathophysiological concentrations reported in the cerebrospinal fluid (CSF). Cytokine-induced anorexia may also participate in the long-term anorexia observed during disease. Here, we studied the effects of chronic intracerebroventricular (ICV) microinfusion (through osmotic minipumps) of various cytokines on feeding and drinking in rats. The results show: IL-1β decreased nighttime feeding dose-dependently (with 0.5, l.0, 2.0, and 8.0 ng/24 h, n ≥ 8/group). The decrease of feeding and corresponding decrease of body weight persisted during the 7-day infusion. Total daily food intake decrease was less prominent relative to the nighttime decrease because daytime food intake slightly increased. Feeding and body weight increased toward baseline following the end of the IL-1β infusion. ICV microinfusion of heat-inactivated IL-1β or IL-1β plus IL-1 receptor antagonist had no effect, suggesting specificity of action of IL-1β. Water intake did not decrease in any IL-1β-β-treated group, suggesting specificity on feeding. Chronic ICV administration of TNF-α (20, 100, or 300 ng/24 h), IL-6 (100 ng/24 h), or IL-8 (20 ng/24 h) was significantly less effective than IL-1β in inducing behavioral modifications. The results suggest that IL-1β, at doses that yield estimated pathophysiological concentrations in the CSF, is capable of inducing long-term anorexia and this effect may participate in the anorexia observed during chronic disease.

Neuropeptide Y (NPY) increases feeding by direct action in the central nervous system (CNS). Interleukin-1 beta (IL-1 beta), on the other hand, induces anorexia when administered ICV at estimated pathophysiological (e.g., yielded by 1.0 ng/rat dose) and pharmacological (> or = 4.0 ng) concentrations in the cerebrospinal fluid (CSF). In the present study, we investigated NPY/IL-1 beta interactions using the ICV administration. ICV microinfusion of NPY (5.0 micrograms) significantly increased 2-h food intake (by 89%), whereas IL-1 beta decreased 2-h food intake (32% decrease with 1.0 ng/rat; 53% with 4.0 ng/rat; and 51% with 8.0 ng/rat). NPY (5.0 micrograms) blocked the anorexic effect induced by all doses of IL-1 beta when both compounds were administered concomitantly. Central infusion of NPY was also able to induce feeding in IL-1 beta-pretreated rats exhibiting marked anorexia. The results show that ICV-administered NPY blocks and reverses the anorexia induced by estimated pathophysiological and pharmacological concentrations of IL-1 beta in rats. A second interpretation of a data subset is that IL-1 beta attenuates or blocks NPY-induced increase in feeding depending on the IL-1 beta dose used. Blockage and reversal of IL-1 beta-induced anorexia by NPY suggest the importance in studying cytokine-peptide interactions in the regulation of feeding behavior. Understanding these endogenous interactions may produce strategies with potential therapeutic implications for chronic diseases associated with long-term anorexia.

Buprenorphine is a synthetic opioid proposed as a potential treatment for drug abuse. Although buprenorphine is widely considered to be a partial agonist at opioid receptors, little is known of its electrophysiological effects in the central nervous system. Because buprenorphine has been reported to have limited hedonic effects in humans, and since activation of the dopaminergic system is thought to be critical to the reinforcing effects of drugs, we compared the ability of buprenorphine and morphine to activate dopamine neurons. We report here that buprenorphine and morphine are equally effective in increasing the impulse flow of dopamine cells in the ventral tegmental area. Extracellular single unit activity was recorded from dopaminergic (DA) neurons in the ventral tegmental area (VTA) of chloral hydrate anethestized rats. Standard physiological and anatomical criteria were used to identify DA neurons. Systemic injection of buprenorphine (5–200 μg/kg, i.v.) and morphine (1–10 mg/kg, i.v.) produced equal magnitudes of activation in a similar subset of DA neurons in the VTA (buprenorphine: 173%; morphine: 164%). Unlike morphine, the activation by buprenorphine was not reversed by the opioid antagonist naloxone (50–100 μg/kg, i.v.), but this is consistent with the known pharmacodynamics of buprenorphine at opioid receptors. These studies demonstrate that acute administration of buprenorphine has morphinelike effects on the impulse activity of DA neurons. The implications for use of buprenorphine as a clinical treatment for drug abuse are discussed. © 1994 Wiley-Liss, Inc.

IL-1beta induces anorexia and adipsia. Here, we report that intracerebroventricular (ICV) pretreatment with an antisense (but not sense) phosphothio-oligodeoxynucleotide to the IL-1 receptor type I (IL-1RI, 1.28 microg or 239 pmol twice daily for 3.5 days before IL-1beta plus antisense) inhibits the anorexia, but not the adipsia induced by the ICV administration of 2.0 ng IL-1beta/rat (a dose that yields estimated pathophysiological concentrations in the cerebrospinal fluid). The mean 2 h food intake decrease in response to IL-1beta was 5.6% (n = 10) in the antisense- and 43% in the sense (n = 9)-treated groups; the mean 2 h water intake decrease was 40% in the antisense- and 39% in the sense-treated groups. The intraperitoneal administration of IL-1RI antisense, in doses equivalent to those administered centrally, had no effect on the anorexic effect induced by ICV administered IL-1beta; this indicates a direct action in the central nervous system. The results suggest that: i) IL-1RI is involved in the short-term anorexigenic, but not the adipsogenic effect induced by centrally administered IL-1beta; and ii) the approach presented using antisense strategies is applicable to study the molecular basis of IL-1 mediated behaviors.

Interleukin (IL)-1 beta, IL-8, and tumor necrosis factor-alpha (TNF-alpha) induce anorexia when administered intracerebroventricularly at doses that yield estimated pathophysiological concentrations reported in the cerebrospinal fluid (CSF). Our hypothesis is that pivotal cytokines released during pathological processes interact to induce anorexia during disease. In the present study, we investigated the effects of the intracerebroventricular microinfusion of individual or multiple combinations (8 dyads and 5 triads) of IL-1 beta, IL-8, and TNF-alpha on feeding and the microstructure of eating in rats maintained ad libitum. Estimated pathophysiological concentrations of cytokine combinations exhibited additive or synergistic activities in inducing anorexia. Computerized analysis of behavioral patterns demonstrated that the most effective treatment (triad of 1.0 ng IL-1 beta + 20 ng IL-8 + 20 ng TNF-alpha/rat, n = 11) decreased nighttime meal size by 42% and feeding rate (meal size/meal duration) by 26%, whereas it increased the satiety ratio (postprandial intermeal intervals/meal size) by 80%; meal duration and meal frequency were not significantly affected. Analysis of meal parameters in 4-h intervals revealed a maximum effect during the first 4-h interval after the intracerebroventricular administration. The time course during this initial 4-h interval analyzed in 10-min periods was similar for IL-8 (n = 10) and TNF-alpha (n = 11), and both were significantly different from the time course induced by IL-1 beta (n = 10) and the most effective triad (n = 11). Intracerebroventricular microinfusion of heat-inactivated triad or intraperitoneal administration of the most effective triad, in doses-equivalent to those administered centrally, had no effect on feeding. The results suggest that estimated pathophysiological concentrations of cytokines in the CSF act centrally and additively or synergistically to decrease feeding, and this effect may participate in the anorexia frequently accompanying pathological processes.