Presence of the μ3 Opiate Receptor in Endothelial Cells

Abstract

Initial confinement of opiate receptors to the nervous system has recently been broadened to several other cell types. Based on the well established hypotensive effect of morphine, we hypothesized that endothelial cells may represent a target for this opiate substance. Endothelial cells (human arterial and rat microvascular) contain a high affinity, saturable opiate binding site presumed to mediate the morphine effects that is stereoselectively and characteristically antagonized by naloxone. This opiate alkaloid-specific binding site is insensitive to opioid peptides. It is, therefore, considered to be the same subtype of opiate receptor (designated 3 ) used in the mediation of morphine in other cell types exhibiting the same binding profile. Experiments with endothelial cultures and the aortic ring of rats cultured in vitro demonstrate that morphine exerts direct modulatory control over the activities of endothelial cells, which leads to vasodilation. It induces the production of nitric oxide, a process that is sensitive to naloxone antagonism and nitric oxide synthase inhibition. In contrast with that of opiates, the administration of opioid peptides does not induce nitric oxide production by endothelial cells. In conclusion, the data presented above reveal a novel site of morphine action, endothelial cells, where a 3 receptor is coupled to nitric oxide release and vasodilation.The vast majority of pharmacological studies of the properties of opiate substances have long been almost exclusively concerned with their effects on analgesic and antinociceptive phenomena. More recently, a number of experiments have demonstrated that morphine modulates the activity of varieties of cell types, among them the immunocytes of several mammalian and invertebrate species (1, 2). In addition, this largely down-regulating effect was found to be mediated by a highly specific, opiate alkaloid-sensitive receptor used selectively by opiates (1, 2). In the present case, the receptor ( 3 ) accomplishes this by counteracting the cellular responsiveness to a number of immunoexcitatory molecules, e.g. lipopolysaccharides and some cytokines (see Ref. 3).In this context, morphine was found to be quite potent in lowering or terminating the activation of human granulocytes and monocytes exposed to the stimulatory activity of plasma obtained from cardiopulmonary bypass patients (4 -7). From these observations, we surmised that a proportion of these cells may have been derived from intravascular immune cells whose adhesiveness to the vascular lining may have been altered by the presence of morphine in this tissue.The present study was aimed at the exploration of the possibility that endothelial cells may be under the direct control of the opiates. It provided evidence for the specific binding of morphine to endothelial cells, resulting in stimulation of nitric oxide (NO) 1 production in a naloxone-reversible manner and relaxation of blood vessels. It also demonstrated that these activities are mediated by the special opiate receptor 3 presen...

Cannabinoid Receptors Are Coupled to Nitric Oxide Release in Invertebrate Immunocytes, Microglia, and Human Monocytes

“…The inhibition of cell spreading (26 -28) is in agreement with observations made in the present study, namely, that anandamide receptor coupling to NO may be the mechanism initiating this cell rounding (6,29). 2 Given the fact that naloxone does not antagonize or bind to the anandamide receptor, these signal systems appear to be distinct.…”

“…Tip diameter of the probe (25 m) permitted the use of a micromanipulator (Zeiss-Eppendorff) attached to the stage of an inverted microscope (Nikon Diaphot) to position the sensor 10 m above the cell surface. Calibration of the electrochemical sensor was performed by the use of different concentrations of nitrosothiol donor S-nitroso-N-acetyl-DL-penicillamine, as previously detailed (6).…”

Opioids Induce Renal Abnormalities in Tumor-Bearing Mice

“…We and others have shown that opioids also induce nitric oxide synthase (NOS), hemoxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) [17,18,19] which are potent vasodilators. Further, we found that morphine promotes cell proliferation and survival in a manner similar to the effects of vascular endothelial growth factor (VEGF) on endothelial cells [18, 20, 21].…”

Opioid Peptides and Innate Immune Response in Mollusc

“…Evidence for the participation of a synthetic analog of [Met]enkephalin ([D-Ala2,Met5] enkephalinamide, DAMA) in immunoregulatory activities, especially cellular adherence and migration, has been obtained in the mollusc Mytilus edulis [30]. The specific function for [Met]enkephalin in immunoregulation, mediated perhaps by a special subtype of delta receptor [31,32]. LPS and opioids can activate distinct populations of Mytilus immunocytes, and distinct immunoactive cell populations seem to exist since apparently different subsets of cells react when exposed to LPS or opioids and the opioid antagonist naloxone [33].…”