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Short Communication Endomorphins, Met-enkephalin, Tyr-mif-1, and the P-glycoprotein Efflux System after Injection of Endomorphin-1 (tyr-pro-trp-phe-nh 2 ), Endo- Morphin-2 (tyr-pro-phe-phe-nh 2 ), Met-enkephalin (tyr-gly-gly- Phe-met-oh), and Tyr-mif-1 (tyr-pro-leu-gly-nh 2 ) into the Lateral Ventri
| Content Provider | Semantic Scholar |
|---|---|
| Author | Abba, Julio Kastin |
| Abstract | The P-glycoprotein (P-gp) transport system, responsible for the efflux of many therapeutic drugs out of the brain, recently has been shown to transport the endogenous brain opiate endorphin. We used P-gp knockout mice (Mdr1a) and their controls to determine where P-gp is involved in the saturable efflux systems of four other endogenous opiate-modulating peptides across the blood-brain barrier (BBB). the disappearance of any of these peptides from the brains of knockout mice compared with their controls. This demonstrates that unlike endorphin and morphine, P-gp does not seem to be required for the brain-to-blood transport of the endomorphins, Met-enkephalin, or Tyr-MIF-1 across the BBB. P-Glycoprotein (P-gp 1) is a transport protein expressed at the capillary endothelial cells that make up the blood-brain barrier (BBB). It can transport a large variety of drugs out of the brain, contributing to what misleadingly seems to be their poor penetration of the BBB Knockout mice have been developed for P-gp, which is encoded in the Mdr1a (multidrug resistance 1a) gene (Schinkel et al., 1994). These mice manifest no basic physiological abnormalities (Schinkel et al., 1997), maintain BBB integrity (de Lange et al., 1998), but show increased opiate-induced analgesia (Thompson et al., 2000) and limited transport of morphine (Xie et al., 1999). Recently, the P-gp system was implicated in the transport of i.c.v. administered endor-phin from the brain into the blood (King et al., 2001), raising the possibility that other endogenous brain opiates might be similarly transported. Endomorphin has higher affinity and is more selective for the -opiate receptor than endorphin (Zadina et al., 1997). A saturable brain-to-blood efflux system has been found for both endomorphin-1 and endomorphin-2 (Kastin et al., 2001). This shared transport system is not cross-inhibited by Tyr-MIF-1, another opiate-modulating tet-rapeptide, which, like the endomorphins, we have isolated from brain tissue (Zadina et al., 1989; Hackler et al., 1995). Tyr-MIF-1 has the first saturable transport system across the BBB to be described for a peptide (Banks and Kastin, 1984); it is extremely stable in cerebro-spinal fluid, and its efflux system does not transport any of the peptide fragments contained within the tetrapeptide even though the transporter is shared with Met-enkephalin (Banks et al., 1986, 1990; Kastin et al., 1994). We investigated whether the P-gp system is involved in the transport of the endomorphins, Met-enkephalin, and Tyr-MIF-1. Materials and Methods Male P-gp knockout mice lacking the Mdr1a gene and their male FVB controls were … |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://dmd.aspetjournals.org/content/dmd/30/3/231.full.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
