μ-Opioid receptor–mediated mechanisms and functions of opioids relevant to sickle cell disease. Binding of opioids to μ-opioid receptors activates multiple signaling pathways that may exaggerate several complications, including increased vascular permeability, endothelial specific activity, stroke, vasodilation, opioid tolerance, retinopathy, renal pathology, and hyperalgesia. The center poppy represents analgesic opioids, including morphine, hydromorphone, and fentanyl. SIP3R, sphingosine 1 phosphate receptor 3.