Opioid Tolerance–In Search of the Holy Grail

Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France.
Cell (Impact Factor: 32.24). 04/2002; 108(5):587-90. DOI: 10.1016/S0092-8674(02)00666-9
Source: PubMed


Tolerance, one of several behavioral adaptations to prolonged opioid treatment, has long been explained by desensitization of opioid receptor signaling and loss of surface receptors. However, recent evidence presents an alternative hypothesis, suggesting that receptor internalization could in fact reduce tolerance in vivo.

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Available from: Chris Evans, Oct 14, 2015
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    • "Upon agonist binding, these receptors couple to G proteins and affect several signal transduction pathways that are thought to mediate the broad range of functions and pharmacological effects of endogenous and exogenous opioids [15]. Previous studies have suggested that the mu opioid receptor (MOR) plays a key role in mediating the major clinical effects of analgesics, such as the effects of morphine, as well as the tolerance and physical dependence that develops after prolonged opioid administration [16]. Recently, a growing body of evidence has suggested that MOR expression is downregulated in the spinal cord [17-21] and dorsal root ganglion [18,21-24] after nerve injury. "
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    ABSTRACT: Background The analgesic potency of opioids is reduced in neuropathic pain. However, the molecular mechanism is not well understood. Results The present study demonstrated that increased methylation of the Mu opioid receptor (MOR) gene proximal promoter (PP) in dorsal root ganglion (DRG) plays a crucial role in the decreased morphine analgesia. Subcutaneous (s.c.), intrathecal (i.t.) and intraplantar (, not intracerebroventricular (i.c.v.) injection of morphine, the potency of morphine analgesia was significantly reduced in nerve-injured mice compared with control sham-operated mice. After peripheral nerve injury, we observed a decreased expression of MOR protein and mRNA, accompanied by an increased methylation status of MOR gene PP, in DRG. However, peripheral nerve injury could not induce a decreased expression of MOR mRNA in the spinal cord. Treatment with 5-aza-2′-deoxycytidine (5-aza-dC), inhibited the increased methylation of MOR gene PP and prevented the decreased expression of MOR in DRG, thereby improved systemic, spinal and periphery morphine analgesia. Conclusions Altogether, our results demonstrate that increased methylation of the MOR gene PP in DRG is required for the decreased morphine analgesia in neuropathic pain.
    Full-text · Article · Aug 2014 · Molecular Pain
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    • "Opioids act primarily through mu opioid (MOP) receptor activation. MOP agonists, such as morphine, are helpful for acute pain conditions but are less effective against chronic pain since tolerance to their analgesic effects can develop, necessitating dose escalation to overcome the tolerance and to maintain the required analgesic efficacy (Kieffer and Evans 2002; Kalso et al. 2004). Although several studies approached the investigation of mechanisms potentially involved in opioid tolerance-related phenomena, they failed to identify a single regulatory mechanism accounting for the tolerance. "
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    ABSTRACT: Recent studies showed that combination of mu opioid receptor (MOP) agonism and monoamine reuptake inhibition may improve the therapeutic effect of opioids by reducing requirement for MOP activation. Tapentadol, showing such a combined mechanism of action, exhibits delayed analgesic tolerance development compared to pure MOP agonists. Here we investigated how opioid receptors are regulated following different schedules (two ranges of concentrations for 24 and 48 h) of tapentadol exposure in vitro in SH-SY5Y cells. MOP and nociceptin/orphaninFQ (NOP) receptor gene expressions were quantified using qReal-Time PCR. Moreover, studies were performed in U2 cells to assess tapentadol effect on MOP internalization compared with morphine and DAMGO. Ten and 100 nM tapentadol for 48 h induced a significant increase of MOP gene expression; cells exposed to 100 μM tapentadol for 24 and 48 h showed a significant increase of MOP mRNA levels. NOP gene expression showed a significant decrease following tapentadol at all low concentrations used after 24 h and at high concentrations (45 and 60 μM) after 24 h and (60 μM) after 48 h. Differently from DAMGO, tapentadol or morphine showed no effects on MOP internalization. This study suggests that tapentadol affects MOP and NOP gene expression and MOP internalization showing a pattern distinct from classical MOP agonists. Whether these differences can explain the improved therapeutic profile of tapentadol remains to be investigated.
    Full-text · Article · Feb 2014 · Journal of Molecular Neuroscience
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    • "The effectiveness of long-term opioid therapy is affected by the development of tolerance to the analgesic effects. Despite several reports approached the study of mechanisms underlying opioid tolerance, this phenomenon is still largely unknown so that its elucidation has been compared to the " search of the Holy Grail " (Kieffer and Evans 2002). Morphine, the prototype of opioids, is broadly employed in many clinical settings; however, its chronic administration rapidly induces tolerance leading to the increase of doses to maintain the required antinociceptive effects. "
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    ABSTRACT: Morphine is widely used for the treatment of severe acute and chronic pain, but long-term therapy rapidly leads to tolerance. Morphine effects are mediated by μ opioid receptor (MOP) activation as well as for fentanyl that, in contrast to morphine, induces less tolerance to analgesia. The mechanisms underlying opioid tolerance involve complex processes, such as MOP desensitization, internalization, and/or changes of gene expression. The development of morphine tolerance also involves adaptive changes of the anti-opioid nociceptin/orphanin FQ-nociceptin receptor system, as suggested by the reduction of morphine tolerance in nociceptin opioid receptor (NOP) knockout mice. The aim of the present study was to investigate the MOP and NOP gene expression in the SH-SY5Y cells following morphine and fentanyl exposure. Results showed that cell exposure to 10 μM morphine for 5 h induced a significant decrease of MOP and NOP gene expression and that the MOP downregulation was reverted by the pretreatment with naloxone. Conversely, SH-SY5Y cells exposed to 0.1 and 1 μM fentanyl for 5 and 72 h showed a significant MOP upregulation, also reverted by naloxone pretreatment. Fentanyl induced no changes of NOP gene expression. The present findings showed a different effect by morphine and fentanyl on MOP mRNA levels that contributes to define the role of MOP gene expression changes in the mechanisms underlying the tolerance. Morphine also triggers an altered NOP-related signaling confirming that the nociceptin/orphanin FQ-nociceptin receptor system also plays a significant role in the development of morphine tolerance.
    Full-text · Article · May 2013 · Journal of Molecular Neuroscience
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