The Emerging Perspective of Morphine Tolerance: MicroRNAs

Figure 1

Schematic detailing the relationship among CaMKII-, BDNF-, and NMDAR-inducing LTP and morphine tolerance. Chronically activated MORs induce increases in Ca²⁺ levels and activation of the CaMKII signaling pathway at synapses, which subsequently triggers the release of BDNF and glutamate. On the one hand, BDNF directly induces LTP through downstream signaling, and, on the other hand, BDNF also upregulates the expression of NMDAR. An activated NMDAR signaling pathway not only directly induces LTP but also upregulates Ca²⁺ levels and activates the CaMKII signaling pathway. Finally, a mutual promotion circuit for CaMKII, BDNF, and NMDAR is formed and brings about morphine tolerance. Multiple miRNAs may be involved in regulating the circuit. MORs, μ opioid receptors; CaMKII, calcium/calmodulin-dependent protein kinase II; TrkB, tyrosine receptor kinase B; BDNF, brain-derived neurotrophic factor; miRNAs, microRNAs; LTP, long-term potentiation; NMDAR, N-methyl-D-aspartate receptor.