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Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction - PubMed

Review

Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction

M J Christie. Br J Pharmacol. 2008 May.

Abstract

A large range of neuroadaptations develop in response to chronic opioid exposure and these are thought to be more or less critical for expression of the major features of opioid addiction: tolerance, withdrawal and processes that may contribute to compulsive use and relapse. This review considers these adaptations at different levels of organization in the nervous system including tolerance at the mu-opioid receptor itself, cellular tolerance and withdrawal in opioid-sensitive neurons, systems tolerance and withdrawal in opioid-sensitive nerve networks, as well as synaptic plasticity in opioid sensitive nerve networks. Receptor tolerance appears to involve enhancement of mechanisms of receptor regulation, including desensitization and internalization. Adaptations causing cellular tolerance are more complex but several important processes have been identified including upregulation of cAMP/PKA and cAMP response element-binding signalling and perhaps the mitogen activated PK cascades in opioid sensitive neurons that might not only influence tolerance and withdrawal but also synaptic plasticity during cycles of intoxication and withdrawal. The potential complexity of network, or systems adaptations that interact with opioid-sensitive neurons is great but some candidate neuropeptide systems that interact with mu-opioid sensitive neurons may play a role in tolerance and withdrawal, as might activation of glial signalling. Implication of synaptic forms of learning such as long term potentiation and long term depression in opioid addiction is still in its infancy but this ultimately has the potential to identify specific synapses that contribute to compulsive use and relapse.

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Figures

Figure 1
Figure 1

Organization of opioid adaptations in the nervous system including: (a) receptor tolerance at the MOPr itself showing loss in the coupling of MOPr to a major cellular effector, the G-protein-regulated inwardly rectifying potassium channel, K+ channel. Several potential mechanisms could account for tolerance at this level of organization, but changes to coupling and perhaps surface expression appear to be most important. (b) Cellular tolerance and withdrawal in opioid-sensitive neurons is due to multiple adaptations to intracellular signalling cascades, but hypertrophy of cAMP signalling is the best established. (c) Systems feedback adaptations in opioid-sensitive nerve and neuroglial networks can develop and contribute to tolerance and withdrawal. (d) Synaptic plasticity and learning in opioid-sensitive nerve networks may involve changes in synaptic plasticity driven by changes in presynaptic release probability, which are well established at many opioid-sensitive GABAergic synapses, but more importantly, mechanisms resembling LTP and/or long-term depression probably involving AMPA receptor insertion in synapses may produce long-term changes in synaptic strength. It should be noted that adaptations outlined in (b) and (c) can strongly influence synaptic plasticity.

Figure 2
Figure 2

Scheme of opioid receptor activation and internalization based on general model developed for the β-adrenergic receptor. Growing evidence suggests that receptor tolerance involves enhancement or acceleration of these processes. Although opioid receptor activation, desensitization and internalization are well established, the precise mechanisms are not clearly known. Desensitization of the receptor certainly precedes internalization, but it is not known whether this is dependent of GRK association and phosphorylation. It is probably not dependent on Arr3 binding because desensitization proceeds in the Arr3 knockout mice. The major initial signalling steps, that is, release of G-protein α and βγ subunit, are attenuated by the enhanced desensitization or internalization, as is signalling downstream from the MOPr-Arr3 complex. Abbreviations: Arr3, arrestin3; GRK, G protein coupled receptor kinase; DYN, dynamin. Adapted from Connor et al., 2004.

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