[Molecular mechanism of morphine tolerance and biological approaches to resolve tolerance].

One of the major problems associated with the chronic use of morphine is tolerance. Repeated uses of morphine to relieve pain often cause patients to develop increasing resistance to the effects of the drugs, so that progressively higher doses are required to achieve the same analgesic effects. Acquired tolerance is thought to be different from dependence or addiction, but molecular mechanism underlying the development of tolerance is still unclear. Tolerance has been explained by desensitization of opioid receptor signaling and loss of functional receptors in the cell surface. The classical hypothesis was that phosphorylation and arrestin binding resulted in uncoupling of the receptor from G proteins, and reduced agonist efficacy. The receptor internalization would then result in fewer functional receptors at the cell surface. These events would cause so-called signaling desensitization. However, recent molecular biological studies have led researchers to revise the classical view of tolerance from observations that morphine does not always promote efficient receptor internalization. Among several key processes, the sequestration and subsequent internalization of the opioid receptor may play an important role for morphine tolerance. In fact, recent studies have suggested that receptor internalization can reduce tolerance. In addition, activation of the NMDA subtype of the glutamate receptor has been suggested as an anti-opioid system in the development of morphine tolerance. In this review, we focus on recent research progress on the morphine tolerance, and molecular biological and clinical approaches to resolve morphine tolerance.