Effect of morphine on lipopolysaccharide-induced tumor necrosis factor-alpha production in vivo: involvement of the sympathetic nervous system.

Morphine treatment modulates a variety of immunological parameters, including tumor necrosis factor-alpha (TNF-alpha) production by activated macrophages in vitro. The aim of our study was to clarify the effect of morphine on lipopolysaccharide (LPS)-induced TNF-alpha production in vivo. Plasma TNF-alpha levels of mice were determined by ELISA. Subcutaneous injection of morphine decreased LPS-induced TNF-alpha production throughout the response, an effect that was dose-dependent and reversible by naloxone. Blockade of the sympathetic transmission by chlorisondamine prevented the inhibitory effect of morphine on TNF-alpha production. It is concluded that (i) systemic administration of morphine inhibits LPS-induced TNF-alpha production in vivo via 'classic' opioid receptors; (ii) this effect requires intact sympathetic outflow. Since the increased incidence of bacterial and viral infections in opioid addicts is well documented, it is suggested that the inhibitory effect of morphine on TNF-alpha production might play a substantial role in the increased vulnerability of these individuals to certain infections.

Modulation of lipopolysaccharide-induced tumor necrosis factor-alpha and nitric oxide production by dopamine receptor agonists and antagonists in mice.

The effects of various agonist and antagonists of dopamine D1 and D2 receptors on lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) production was investigated in mice. Pretreatment of animals with bromocryptine or quinpirole, agonists of dopamine D2 receptors caused a blunting of both the TNF-alpha and NO responses to LPS injected intraperitoneally. Sulpiride, an antagonist of dopamine D2 receptors, decreased the LPS-induced TNF-alpha plasma levels in a dose-dependent manner and inhibited the LPS-induced NO production by peritoneal macrophages. Bromocryptine or quinpirole blunted both the TNF-alpha and NO response to LPS. SCH-23390, an antagonist of dopamine D1 receptors did not alter LPS-induced TNF-alpha production, but inhibited LPS-induced NO production. These results indicate that while the D2 subtype of dopamine receptors is involve in the modulation of both LPS-induced TNF-alpha and NO production, dopamine D1 receptors only regulate the production of NO. Since several drugs possess effect on dopamine D2 receptors, the present observations may be of clinical relevance.

alpha 2-, alpha 2A-, alpha 2B/2C-Adrenoceptor subtype antagonists prevent lipopolysaccharide-induced fever response in rabbits.

Exogenous pyrogens, e.g., bacterial lipopolysaccharides (LPS), are thought to stimulate macrophages to release endogenous pyrogens, e.g., TNF alpha, IL-1 beta, and IL-6, which act in the hypothalamus to produce fever. We studied the effect of different alpha 1- and alpha 2-adrenoceptor subtype antagonists, applied intraperitoneally, on the febrile response induced by LPS in rabbits. Evidence was obtained that prazosin, an alpha 1- and alpha 2B/2C-adrenoceptor antagonist; WB-4101, an alpha 1- and alpha 2A-adrenoceptor antagonist; CH-38083, a highly selective alpha 2-adrenoceptor antagonist (alpha 2:alpha 1 > 2000); BRL-44408, an alpha 2A-adrenoceptor antagonist; and ARC-239, an alpha 2B/2C- and also alpha 1-adrenoceptor antagonist, blocked the increase of colonic temperature of the rabbit produced by 2 micrograms/kg LPS administered intravenously without being able in themselves to affect colonic temperature. In addition, prazosin, WB-4101 and CH-38083 antagonized the fall in skin temperature that occurred at the time when the colonic temperature was rising in control animals injected with LPS. All these results suggest that norepinephrine, through stimulation of both alpha 1- and alpha 2- (alpha 2A- and alpha 2B/2C-) adrenoceptor subtypes, is involved in producing fever in response to bacterial LPS.

Dopamine, as well as norepinephrine, is a link between noradrenergic nerve terminals and splenocytes.

The effect of supramaximal electric field stimulation on 3H released from rat spleen strips was studied after loading with either [3H]dopamine ([3H]DA) or [3H]norepinephrine ([3H]NE). In some experiments, [3H]DA and [3H]NE stored in the tissue or released in response to electrical stimulation were separated from their tritiated metabolites using HPLC followed by radiochemical detection. The stimulation-evoked release of 3H after loading with either derivative was subject to negative feedback modulation through alpha2-adrenergic, D2-dopamine and muscarinic acetylcholine receptors, and could be prevented by either calcium removal or tetrodotoxin blocking of Na+ influx, indicating its neuronal and vesicular origin. After the separation of radioactive metabolites by HPLC, both the tissue loaded with [3H]DA and the fractions collected during electrical stimulation contained a considerable amount of [3H]NE, providing evidence that the neurons it originated from were adrenergic in function. [3H]DA was also released during electrical stimulation. Since the spleen does not receive dopaminergic innervation, it was concluded that the noradrenergic axon terminals in the spleen were able to take up DA, convert it in part into NE, and release it as both DA and NE in response to neural activity. The ratio of [3H]DA and [3H]NE in the spleen loaded with [3H]DA was found to be dependent on both temperature and time of loading, and could be modulated by various drugs such as desmethylimipramine, a NE uptake blocker, and disulfiram or fusaric acid, dopamine beta-hydroxylase inhibitors. The phenomenon may reveal a new mechanism by which immunocytes in the spleen can be regulated by the neuroendocrine system.

Na+ channel block prevents the ischemia-induced release of norepinephrine from spinal cord slices.

The principal finding of the present study with rat spinal cord slices was the novel demonstration of the [Ca2+]o-independent effect of ischemia on norepinephrine release and its antagonism by tetrodotoxin and low temperature (10 degrees C). Our finding that tetrodotoxin antagonized the effects of glucose deprivation on norepinephrine release in a [Ca2+]o-independent way suggests that Na+ channel block alone, i.e., the prevention of Na+ accumulation, may account for the protective action. Low temperature completely prevented the effect of ischemia on norepinephrine release but did not change the release associated with axonal activity. This finding is in good agreement with the observation that small changes in brain temperature critically determine the extent of neuronal injury from ischemia and suggests that both [Ca2+]o-independent release and cell injury are associated with the norepinephrine membrane carrier. It is suggested, therefore, that drugs able to attenuate the increase in [Na+]i during ischemia may be useful agents to protect against ischemic damage if given before the insult.