| First Author | Garzón-Niño J | Year | 2022 |
| Journal | Int J Mol Sci | Volume | 24 |
| Issue | 1 | PubMed ID | 36614024 |
| Mgi Jnum | J:332614 | Mgi Id | MGI:7426685 |
| Doi | 10.3390/ijms24010582 | Citation | Garzon-Nino J, et al. (2022) (alpha)N-Acetyl beta-Endorphin Is an Endogenous Ligand of sigma1Rs That Regulates Mu-Opioid Receptor Signaling by Exchanging G Proteins for sigma2Rs in sigma1R Oligomers. Int J Mol Sci 24(1) |
| abstractText | The opioid peptide beta-endorphin coexists in the pituitary and brain in its (alpha)N-acetylated form, which does not bind to opioid receptors. We now report that these neuropeptides exhibited opposite effects in in vivo paradigms, in which ligands of the sigma type 1 receptor (sigma1R) displayed positive effects. Thus, (alpha)N-acetyl beta-Endorphin reduced vascular infarct caused by permanent unilateral middle cerebral artery occlusion and diminished the incidence of N-methyl-D-aspartate acid-promoted convulsive syndrome and mechanical allodynia caused by unilateral chronic constriction of the sciatic nerve. Moreover, (alpha)N-acetyl beta-Endorphin reduced the analgesia of morphine, beta-Endorphin and clonidine but enhanced that of DAMGO. All these effects were counteracted by beta-Endorphin and absent in sigma1R(-/-) mice. We observed that sigma1Rs negatively regulate mu-opioid receptor (MOR)-mediated morphine analgesia by binding and sequestering G proteins. In this scenario, beta-Endorphin promoted the exchange of sigma2Rs by G proteins at sigma1R oligomers and increased the regulation of G proteins by MORs. The opposite was observed for the (alpha)N-acetyl derivative, as sigma1R oligomerization decreased and sigma2R binding was favored, which displaced G proteins; thus, MOR-regulated transduction was reduced. Our findings suggest that the pharmacological beta-Endorphin-specific epsilon receptor is a sigma1R-regulated MOR and that beta-Endorphin and (alpha)N-acetyl beta-Endorphin are endogenous ligands of sigma1R. |
