Positive allosteric modulation of µ-opioid receptor – A new possible approach in the pain management?

The antinociceptive effect of the opioid drugs is achieved through activation of the µ-opioid receptor (MOP). The orthosteric and allosteric sites of opioid receptors may be modulated, orthosteric site by endogenous i.e.β-endorphin and exogenous opioids (morphine, oxycodone, fentanyl); whereas BMS-986121, BMS-986122, Comp5, MS1, Ignavine or even oxytocin act on the allosteric site of the MOP. Opioid therapy is associated with numerous side effects, such as: respiratory depression, sedation, constipation, and importantly, prolonged therapy can influence the development of tolerance, overdose, and addiction. Opioid tolerance is a result of MOP internalization and desensitization, preceded by MOP phosphorylation, performed by protein kinases such as: PKA, PKC, GRKs or CaMKII. In vitro and in vivo data suggest that positive allosteric modulators may enhance antinociception triggered by orthosteric ligands and reduce side effects, which would allow the dose of opioids to be reduced and thus provide a more effective therapy. In this review, we present that positive modulation of the allosteric sites of MOP may constitute a new strategy for pain therapy.