Methionine-Enkephalin Stimulates Hydrogen Peroxide and Nitric Oxide Production in Rat Peritoneal Macrophages: Interaction of μ, δ and κ Opioid Receptors

Abstract

Objective: Methionine-enkephalin (MET) modulates various functions of macrophages related to both immune and inflammatory reactions in a naloxone reversible manner, suggesting that opioid receptors are involved in the regulation of macrophage activity. Since an endogenous opioid ligand might interact with more than one type of opioid receptor, the receptor interaction determines its effect on a particular function. Methods: In the present study we have investigated the involvement of different opioid receptor types/subtypes in MET-induced modulation of H₂O₂ and NO production in macrophages. Thioglycollate-elicited or resident rat peritoneal macrophages were treated in vitro with MET and/or specific antagonists of δ_1,2, δ₁, δ₂, µ and ĸ opioid receptors. Results: MET increased H₂O₂production inphorbol myristate acetate-stimulated rat peritoneal macrophages mainly through δ₁ opioid receptor. MET also enhanced NOproduction in rat peritoneal macrophages stimulated with lipopolysaccharide through δ₁ and µ opioid receptors. The blockade of µ and ĸ receptor facilitated a potentiating effect of MET on H₂O₂ release, and blockade of ĸ receptor further raised the MET-induced increase of NO production in macrophages. Conclusion: It is concluded that both negative and positive functional interaction between δ, µ and ĸ opioid receptors regulate the influence of MET on H₂O₂ and NO production in rat peritoneal macrophages.

The Opioid Antagonist Naltrexone Improves Murine Inflammatory Bowel Disease

“…In fact, [Met 5 ]-enkephalin knock-out mice exhibit a defect in T-lymphocyte activation and a reduced ability of Tlymphocytes to proliferate (Hook et al, 2003). Both endogenous and exogenous opioids have been shown to intensify the production of pro-inflammatory cytokines by immune cells and, in some cases, this opioid-stimulated increase in cytokines has been abrogated by opioid receptor antagonists (Vujic et al, 2004). Third, while opioid peptides do not, in themselves, induce inflammatory responses, they can sensitize T-lymphocytes and macrophages to other pro-inflammatory stimuli (Hucklebridge et al, 1990;Kamphuis et al, 1998).…”

“…In vivo treatments with opioids have been shown to induce the release of pro-inflammatory cytokines, such as IL-12 and TNFα, by mouse peritoneal macrophages (Tomassini et al, 2003). Studies have verified similar roles with endogenous opioids, demonstrating that opioids, including [Met 5 ]-enkephalin, stimulate peritoneal macrophages in rodents systems (Vujic et al, 2004). Opioid receptors are found throughout the gastrointestinal tract in the myenteric and submucosal plexus as well as in epithelial cells (Jimenez et al, 2006).…”

The influence of stress and methionine-enkephalin on macrophage functions in two inbred rat strains

“…In vitro supplementation of ME to cells that have already been exposed to different stress mediators, including ME, may result in the activation of specific δ opioid receptors (Radulović et al, 1995), the activation of more than one type of opioid receptor (Vujić et al, 2004) or in the activation of opioid receptor complexes in cell membranes (Boyadjieva et al, 2004). It appears that opioid receptors can form complex hetero-oligomers with other receptors, such as β-adrenergic receptors (Jordan et al, 2001).…”

Evaluation of therapeutic effect of low dose naltrexone in experimentally-induced Crohn's disease in rats

“…MOR expression increases in rat paw model [49] and intestinal inflammation [50]. Enkephalins stimulate the production of hydrogen peroxide, nitric oxide dna induce the release of pro-inflammatory cytokines such as IL -21 and TNFα in rodent peritoneal macrophages [51]. Opioids have been shown to decrease cell growth [52] so naltrexone may be playing a role in mucosal healing.…”