 The most important regulatory proteins for the MOR are the β-arrestins arrestin beta 1 and arrestin beta 2, and the RGS proteins RGS4, RGS9-2, RGS14, and RGSZ2.Long-term or high-dose use of opioids may also lead to additional mechanisms of tolerance becoming involved.This includes downregulation of MOR gene expression, so the number of receptors presented on the cell surface is actually reduced, as opposed to the more short-term desensitisation induced by β-arrestins or RGS proteins.