[Cellular mechanism of opioid tolerance].
Opioids relieve painful stimuli by interacting with the opioid receptor subtypes, mu, delta, and kappa, in brain regions and spinal cord. Tolerance reduces medication effectiveness and causes a right-hand shift in the dose-response curve. The mechanisms involved in the development of opioid tolerance remain not clear. Following long-term opioid treatment, either a decrease or increase in opioid receptors was demonstrated, depending on the types or subtypes of receptors and the central areas to which they are distributed. Opioid receptors, like most other hormone and neurotransmitter receptors, have been shown to mediate their effects through guanine nucleotide binding protein (G protein). Studies regarding chronic treatment with opioid agonists suggest that the uncoupling of the opioid receptors from their corresponding G protein may play an important role in opioid tolerance. The NMDA (N-methyl-D-aspartate) receptors have also been demonstrated involving not only in nociception and pain processing but also in the development of opioid tolerance. The sustained potentiation of NMDA receptor-mediated responses may be provided through activation of PKC (protein kinase C). Furthermore, NMDA receptor-mediated intracellular translocation and activation of PKC may be a critical step in the development of opioid tolerance. The NMDA receptors can also induce the synthesis of NO (nitric oxide) through the activation of NOS (NO synthase). NOS inhibitors were also shown to prevent the development of opioid tolerance, therefore, NO was suggested to play a role in opioid tolerance development. Although much evidence indicates the reasons of opioid tolerance, it is still worth further investigation to explore the mechanisms of multiplicity of opioid receptors and complexity of intracellular biochemical events.