N-alpha-Acetyl beta-Endorphin Is an Endogenous Ligand of sigma 1Rs That Regulates Mu-Opioid Receptor Signaling by Exchanging G Proteins for sigma 2Rs in sigma 1R Oligomers

The opioid peptide beta-endorphin coexists in the pituitary and brain in its N-alpha-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 (sigma 1R) displayed positive effects. Thus, N-alpha-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, N-alpha-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 sigma 1R(-/-) mice. We observed that sigma 1Rs negatively regulate mu-opioid receptor (MOR)-mediated morphine analgesia by binding and sequestering G proteins. In this scenario, beta-Endorphin promoted the exchange of sigma 2Rs by G proteins at sigma 1R oligomers and increased the regulation of G proteins by MORs. The opposite was observed for the N-alpha-acetyl derivative, as sigma 1R oligomerization decreased and sigma 2R 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 sigma 1R-regulated MOR and that beta-Endorphin and N-alpha-acetyl beta-Endorphin are endogenous ligands of sigma 1R.