**3.7 Receptor dimerization and immune cell stimulation and functioning**

Chemokines are chemotactic cytokines that mediate their effects on leukocytes through a number of G protein-coupled, seven transmembrane-spanning (STM) receptors [84]. Specificity is provided by patterns of receptor and G protein expression, ligand potency, and levels of receptor desensitization. Interactions among receptors are mediated through a process known as receptor cross regulation, or heterologous desensitization [85]. Ali et al*.* [86] showed that thrombin receptor activation causes phosphorylation of several chemoattractant receptors, including the IL-8 receptor CXCR1, the C5a receptor, and the receptor for platelet-activating factor 3. Ben-Baruch et al*.* [87] have shown that homologous desensitization through phosphorylation of the IL-8 receptor CXCR2 occurs in response to its native ligands IL-8 and neutrophil-activating peptide (NAP)-2. Grimm et al*.* [28] showed that opiates, acting through δ and μ subclasses of opioid receptors expressed on human monocytes and neutrophils, are capable of inhibiting subsequent migratory responses to chemokines, and that this process of heterologous desensitization or trans-deactivation is associated with phosphorylation of chemokine receptors. Szabo et al*.* [88] showed that the chemotactic activities of both μ- and δ-OR are desensitized following activation of the chemokine receptors CCR5, CCR2, CCR7, and CXCR4 but not of CXCR1 or CXCR2 receptors. The inhibition of CCL3 and CCL5 responses following opioid pretreatment is consistent with the desensitization of either CCR1 or CCR5 or both. This receptor cross talk results in heterologous desensitization and phosphorylation of some of the chemokine receptors, which subsequently contribute to the immunosuppressive effects of the opioids.
