Improving opioid analgesia: Modulation of the mu-opioid receptor phosphorylation state via combination therapy

Opioid analgesics are commonly prescribed to mitigate pathological pain. In addition to its analgesic effect, this pharmaceutical treatment program is well-known for its ability to induce adverse effects, including opioid-induced hyperalgesia (OIH) and analgesic tolerance. Thus, novel effective therapeutic strategies are urgently needed to improve opioid analgesia while mitigating side effects to ensure patient safety. Currently, efforts to increase the benefit/risk profiles of opioid analgesics, particularly combination pharmacotherapy, are highly promising and have made great progress. When combined, opioid analgesics and certain types of nonopioids have been found to reduce the required analgesic dose and decrease dose-limiting side effects compared with monotherapy. However, little is known about the mechanisms that underlie synergistic analgesia. The desensitization and internalization of the mu-opioid receptor (μOR), which is controlled by carboxyl-terminal phosphorylation, limits the efficacy of opioid drugs and underlies the initiation of analgesic tolerance and OIH. Here, we survey the synergistic effects of opioid and nonopioid combinations in pain treatment; these combinations improve opioid analgesia and reduce side effects by modulating μOR phosphorylation and dephosphorylation. Furthermore, we discuss how these nonopioid receptors and their agents are involved in the regulation of protein kinase-mediated μOR phosphorylation and protein phosphatase-mediated μOR dephosphorylation.