Peptides 23 (2002) 1597–1605 Different effects of methionine-enkephalin on paw edema in two inbred rat strains Stanislava Stanojevi´ c a,∗ , Jelena Radulovi´ c b , Vesna Kovaˇ cevi´ c-Jovanovi´ c a , Vesna Vuji´ c c , Mirjana Dimitrijevi´ c a a Branislav Jankovi´ c Immunology Research Center, Torlak Institute of Immunology and Virology, 458 Vojvode Stepe, 11152 Belgrade, Yugoslavia b Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, 35075 Goettingen, Germany c Instituteof Chemistry, Faculty of Medicine, Belgrade, Yugoslavia Received 28 January 2002; accepted 19 April 2002 Abstract The effect of intraplantarly (i.pl.)-injected methionine-enkephalin (ME) on Concanavalin A (Con A)-induced paw edema in Dark Agouti (DA) and Albino Oxford (AO) rats was investigated. ME suppressed edema in DA rats, which was antagonized with naloxone (non-selective opioid receptor antagonist) and naltrindole ( opioid receptors antagonist). Potentiating effect of ME in AO rats was blocked by naloxone, nor-binaltorphimine ( opioid receptors antagonist) and -funaltrexamine ( opioid receptors antagonist). Dexamethasone suppressed edema in both rat strains. These findings suggest that strain-dependent differences in the effects of ME on inflammation in DA and AO rats could be related to diversity in opioid receptors expression in these strains. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Methionine-enkephalin; Naloxone; Naltrindole; nor-Binaltorphimine; -Funaltrexamine; Concanavalin A; , ,  Opioid receptors; Paw edema; Rat strain 1. Introduction Local inflammatory reaction prevents spreading of the infection through the body, thus being regarded as bene- ficial to organisms’ survival and well-being. Inflammation comprises the cascade of events that are driven by both the inflammatory cells, like macrophages and neutrophils, and their soluble products, cytokines. Cell influx to the affected area is controlled by dual action of plasma kinins and arachidonic acid metabolites that beside their chemotactic properties for macrophages and monocytes also dilate local microvasculature. Macrophages, in turn, release cytokines like interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF) [1], providing signals for subsequent complex cel- lular cytokine cascade reactions that result in the selective expression of adhesive molecules [19]. These molecules mediate point-to-point interactions of circulating lympho- cytes, monocytes and neutrophils with endothelium and promote migration of cells toward inflammatory insult in the tissue [19]. The changes in the permeability of the microvasculature promote tissue swelling, redness and heat [8], while local ∗ Corresponding author. Tel.: +381-11-467-465; fax: +381-11-471-838. E-mail address: canac@eunet.yu (S. Stanojevi´ c). release of substance P (SP) from the nerve endings, aside from contributing to increase in vascular permeability [35], initiate pain sensations [38]. Inflammatory reactions are controlled both by immune- derived components of the local milieu and neuroendocrine- derived factors that all together complexly regulate outcome of the local response. For example, corticotropin-releasing hormone (CRH), declared as antiinflammatory hormone ac- cording to its ability to induce the release of glucocorticoids in the periphery, excessively promote inflammatory cascade when locally expressed in the inflamed tissue [16]. But, when injected into the inflamed rat paws CRH induce release of opioid pentapeptide methionine-enkephalin (ME) from im- mune cells, which subsequently produce antinociception that improves clinical symptoms of inflammation [34]. Apart from its well-known activities in the central ner- vous system, ME was shown to modulate inflammatory im- mune reactions in the rat. Both low-dose-induced increase and high-dose-induced decrease of inflammatory reactions, observed after intracerebroventricular and systemic appli- cation of ME, were mediated through  opioid receptors [13,14,42]. Taking into account that opioid peptides were detected in the immune cells at the site of inflammation [34], and that development of inflammatory reactions in- creased the density of opioid receptors in the tissue of the 0196-9781/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII:S0196-9781(02)00105-5