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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.

In a previous study we demonstrated that mice pretreated with the highly selective alpha 2-adrenoceptor antagonist CH-38083 showed blunting of the tumor necrosis factor-alpha (TNF-alpha) response induced by bacterial lipopolysaccharide (LPS). In the present study, the effect of a selective block of alpha 2-adrenoreceptors and the role of the sympathetic nervous system (SNS) in the regulation of LPS-induced TNF-alpha production was explored further using different selective adrenoceptor antagonists and agonists. While adrenalectomy did not prevent the effect of CH-38083, the block of the sympathetic transmission by chlorisondamine fully abolished the inhibitory effect of CH-38083 on LPS-induced TNF-alpha production, suggesting that the effect of the alpha 2-adrenoceptor blocking agent is corticosteroid-independent, but it requires intact sympathetic activity. Since the selective block of alpha 2-adrenoceptors results in an increased sympathetic activity and an increase of the release of noradrenaline (NA) in both the central and the peripheral nervous systems, and in our experiments propranolol, a non-selective beta-adrenoceptor antagonist, and atenolol, a selective antagonist of beta 1-adrenoceptors, prevented the effect of alpha 2-adrenoceptor blockade by CH-38083 of the TNF-alpha response induced by LPS, it seems likely that the excessive stimulation by NA of beta 1-adrenoceptors is responsible for this action. The role of beta-adrenoceptors and endogenous catecholamines is further substantiated by the finding that pretreatment of animals with propranolol alone resulted in a dose-dependent increase of the TNF-alpha response induced by LPS, and that isoproterenol, a non-selective beta-adrenoceptor agonist, decreased it.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of tumor necrosis factor-alpha (TNF-alpha) on the stimulation-evoked release of noradrenaline (NA) from isolated rat median eminence (ME) was investigated, using a low-volume perfusion system. Median eminence, loaded with [3H]noradrenaline, was superfused with Krebs solution and stimulated electrically (2 Hz, 120 shocks). The effect of TNF-alpha was studied on the S2/S1 ratio. It was found that stimulation-evoked release of NA from noradrenergic axon terminals in the isolated rat ME was inhibited by TNF-alpha and this effect was concentration-dependent. In contrast, TNF-alpha had no effect on the release of [3H]NA from the spleen. Since NA released in the ME might be involved in the modulation of corticotropin-releasing factor (CRF) production, it is suggested that TNF-alpha, through presynaptic modulation of NA release from noradrenergic nerve terminals in the ME, might regulate CRF and other neurohormone release in this hypothalamic structure.