Effects of in Vitro and in Vivo Opioids on the Production of IL‐12 and IL‐10 by Murine Macrophages

Abstract

We evaluated the ability of the specific micro opioid receptor agonist DAMGO, the kappa-specific agonist U-50488 in vitro, and exogenous opioid morphine administered in vivo both acutely and chronically to modulate IL-12 and IL-10 production by murine peritoneal macrophages. Damgo and U-50488 at the concentrations of 10(-6) and 10(-8) M decreased the production of IL-12 without affecting IL-10. One hour after the acute administration of 5, 10, and 20 mg/kg of morphine a dose-related decrease of both IL-10 and IL-12 levels was present. The pretreatment with naltrexone at doses up to 20 mg/kg did not prevent the decrease of IL-10 and IL-12 induced by morphine. When the drug was administered chronically, a differential development of tolerance to the immune effects was observed. After 3 days of treatment the effect of the acute challenge with 20 mg/kg of morphine on IL-12 was lost. In contrast, morphine-induced inhibition of IL-10 disappeared between 10 and 12 days of treatment, in parallel with tolerance to the antinociceptive effect. These results suggest that opioids modulate macrophage cytokine production. However, the effects exerted by the in vivo administration of morphine are not superimposable onto those induced by the in vitro administration of specific opioid agonists.

Enkephalin, its precursor, processing enzymes, and receptor as part of a local opioid network throughout the respiratory system of lung cancer patients

“…Up to now, expression of ENK with its key processing enzymes within monocytes/macrophages has been described in other systems, for example, in inflamed skin [10] and in spleen [22]. In functional studies, δ opioid agonists seem to modulate macrophage function such as cytokine release, chemokine production, chemotaxis, and phagocytic capacity [23,24]. Alveolar macrophages are known to orchestrate the pulmonary immune response to scavenge particulates, kill microorganisms, and maintain lung parenchyma.…”

Modulation of Immune Function by Morphine: Implications for Susceptibility to Infection

“…Morphine has been shown to alter a number of macrophage functions in humans, rodents, monkeys, and swine. These include phagocytosis (Szabo et al 1993;Tubaro et al 1987;Tomei and Renaud 1997;Tomassini), tumoricidal activity (Koff and Dunegon 1985), nitric oxide (NO) production (Fecho et al 1994;Pacifici et al 1995;Stefano et al 2001;Wang et al 2002), superoxide formation (Sharp et al 1985;Bhat et al 2004), and cytokine expression (Bhat et al 2004;Bian et al 1995;House et al 1995;Thomas et al 1995;Bussiere et al 1993;Alicea et al 1996;Sacerdote 2003). Both chronic and acute exposure to morphine result in inhibition of phagocytosis in humans and rodents.…”

Opioids As Modulators of Cell Death and Survival—Unraveling Mechanisms and Revealing New Indications

“…Morphine had biphasic (Pacifici et al, 2000a) or conflicting effects on cytokine release (Raghavendra et al, 2002;Sacerdote, 2003;Roy et al, 2004). In most studies, immune-modulating effects were inhibited with opioid receptor antagonists and decreased in part with prolonged treatment (Sacerdote, 2003), suggesting that the effects are mediated through "typical" opioid receptors and are subject to opioid tolerance.…”

“…However, there are also functional overlaps between MOR and KOR. For example, IL-12 release from mouse peritoneal macrophages was reduced with both the MOR agonist DAMGO and the KOR agonist U50,488H (Sacerdote, 2003). Morphine had biphasic (Pacifici et al, 2000a) or conflicting effects on cytokine release (Raghavendra et al, 2002;Sacerdote, 2003;Roy et al, 2004).…”

“…In addition to the hormone-mediated "indirect" modulation of cell proliferation, opioids modify T-and B-cell responses (Guan et al, 1997;Shahabi et al, 2000;Beagles et al, 2004;Roy et al, 2004), macrophage and microglial activity (Belkowski et al, 1995;Hu et al, 2000;Hu et al, 2002), chemotaxis (Szabo et al, 2002), cell migration (Patel et al, 2003), and natural killer cell cytotoxicity (Hsueh et al, 1996;Boyadjieva et al, 2001;Yeager et al, 2002) by modifying cytokine and chemokine release (Belkowski et al, 1995;Alicea et al, 1996;Kong et al, 1997;Wetzel et al, 2000b;Sacerdote, 2003), respective receptor expression (Zhang and Rogers, 2000), and chemokine receptor responsiveness (Grimm et al, 1998a;Rogers et al, 2000;Szabo et al, 2002Szabo et al, , 2003Chen et al, 2004) (for review, see McCarthy et al, 2001 and. These effects do not necessarily affect survival of the opioid-stimulated cell but may modify the course of inflammatory and infectious diseases, such as HIV infection, and thereby survival of the organism.…”