Opiate Inhibition of Chemokine‐Induced Chemotaxis

Abstract

Chemokines consist of a family of 8-16-kDa cytokines that are generated very early in a wide variety of inflammatory responses and attract leukocytes to local sites. At nanomolar concentrations chemokines initiate signal transduction and activate leukocytes through seven transmembrane receptors (STM), but higher micromolar doses result in homologous desensitizing effects. On the basis of reports that opiates have anti-inflammatory effects and also use STM, we have investigated the possibility that they may cross-desensitize the response of leukocytes to chemokines. We have confirmed previous observations that met-enkephalin (MET) is chemotactic for human peripheral blood monocytes. Furthermore, we observed that preincubation of monocytes or neutrophils with MET or morphine prevented their subsequent chemotaxis in response to chemokines (MIP1 alpha or IL-8). However, MET did not inhibit the chemotactic response of PMN to NAP-2, a homologous chemokine that is less potent than IL-8 but cannot be desensitized. The inhibitory effect of opiates on chemokine-induced chemotaxis was antagonized by naloxone. Since MIP-1 alpha and IL-8, unlike NAP-2, have the capacity to desensitize leukocytes, it is possible that opiates, by desensitizing some chemokine responses, can suppress inflammatory reactions.

Heterologous desensitization of IL-8-mediated chemotaxis in human neutrophils by a cell-binding fragment of fibronectin

“…These results demonstrate that the inhibitory effects on IL-8-mediated chemotaxis by the cell-binding fragment of FN was limited to the CXCR1 because the 120-kDa FN fragment had no effect on CXCR2-mediated chemotaxis as tested with the CXCR2-specific chemokine MGSA/GRO␣. Such receptor specificity for desensitization toward IL-8 was recently observed by Grimm et al [23] who demonstrated that met-enkephalin and morphine will inhibit IL-8-mediated chemotaxis but do not affect chemotaxis to the CXCR2-specific chemokine, neutrophil activating peptide-2. Known mechanisms responsible for the desensitization of chemokine receptors involve either down-regulation of the receptor from the cell surface via internalization and/or inhibition of signal transduction pathways as a result of [24] have demonstrated during homologous desensitization of the human CXCR1 receptor by IL-8 that the receptor is susceptible to phosphorylation and has identified specific serine and threonine residues on the cytoplasmic tail of CXCR1 that were required for phosphorylation.…”

Cell Surface-Expressed Moesin-Like Receptor Regulates T Cell Interactions with Tissue Components and Binds an Adhesion-Modulating IL-2 Peptide Generated by Elastase

“…Recently, fMLP was observed to inhibit leukocyte migration induced by the subsequent exposure of the cells to either IL-8 or leukotriene B 4 (22). Opiates, which induce chemotaxis of monocytes, inhibit cell migration induced by chemokines (25). Substance P, which by itself does not induce T cell adhesion to ECM, inhibits RANTES-and MIP-1␤-induced T cell adhesion to FN (26).…”

Morphine Regulates Gene Expression of α- and β-Chemokines and Their Receptors on Astroglial Cells Via the Opioid μ Receptor

“…Opioids can modulate the immune response by indirect and direct mechanisms (27,28). Indirect modulation occurs when activation of opioid receptors within the CNS modifies the activity of neuroendocrine axes or neurotransmission pathways and then secondarily affects immune functions (27,28). Direct modulation results from the effects of opioids on cells of the immune system, resulting in their dysregulation (22).…”

“…Morphine can cross the blood brain barrier in sufficient amounts to affect brain function (25,26). Opioids can modulate the immune response by indirect and direct mechanisms (27,28). Indirect modulation occurs when activation of opioid receptors within the CNS modifies the activity of neuroendocrine axes or neurotransmission pathways and then secondarily affects immune functions (27,28).…”