Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation

doi:10.1016/j.tips.2016.08.002

Trends in Pharmacological Sciences

Volume 37, Issue 11, November 2016, Pages 963-976

https://doi.org/10.1016/j.tips.2016.08.002 Get rights and content

Trends

Behavioral tolerance to opioids results from many interacting processes including desensitization, resensitization, and cellular and pass-forward allostasis.

Opioid-biased agonism presents new pharmacological approaches to avoid detrimental side effects and negate aspects of opioid tolerance and dependence.

Negative affect is an opponent process that creates behavioral tolerance to the rewarding effects of opioid drugs, and constitutes a likely driver of relapse following drug cessation.

Microglia activation following chronic opioids is a potential therapeutic target contributing to behavioral tolerance and dependence mechanisms.

Mechanisms of opioid tolerance have focused on adaptive modifications within cells containing opioid receptors, defined here as cellular allostasis, emphasizing regulation of the opioid receptor signalosome. We review additional regulatory and opponent processes involved in behavioral tolerance, and include mechanistic differences both between agonists (agonist bias), and between μ- and δ-opioid receptors. In a process we will refer to as pass-forward allostasis, cells modified directly by opioid drugs impute allostatic changes to downstream circuitry. Because of the broad distribution of opioid systems, every brain cell may be touched by pass-forward allostasis in the opioid-dependent/tolerant state. We will implicate neurons and microglia as interactive contributors to the cumulative allostatic processes creating analgesic and hedonic tolerance to opioid drugs.

Section snippets

What is Tolerance?

Tolerance (see Glossary) is defined as a reduction in effect following prolonged drug administration that results in a loss of drug potency indicated by a pharmacological shift to the right in the dose–response curve. The development and extent of tolerance are dependent on the drug interactions with the opioid receptor(s), dose, and frequency of administration. There are many mechanisms that can contribute to opioid tolerance at a behavioral level, including upregulation of drug metabolism

Cellular Allostasis and the Opioid Receptor Signalosome (MOP and DOP)

Mechanisms of opioid receptor desensitization and resensitization have been thoroughly reviewed for different agonists at the MOP [13]. The ability of different agonists to induce receptor internalization has been shown to affect divergent downstream regulatory processes contributing to the activity of the opioid receptor signalosome and cellular tolerance (Figure 1). Many other processes contribute to cellular allostasis. MOP signaling initiates a cascade of cellular adaptations involving

The Complex Role of Arrestins in Behavioral Tolerance to Opioids

Following the initial report that mutant mice lacking arrestin 3 (β-arrestin 2) exhibit attenuated tolerance to morphine [18], there is now a plethora of studies demonstrating the involvement of arrestins in opioid receptor desensitization and tolerance. Both high- and low-internalizing MOP and DOP agonists induce analgesic tolerance 19, 20, 21, 22, albeit via different mechanisms. Moreover, MOP receptor agonists, independently of their internalization efficacy, exhibit comparable symptoms of

Opponent Processes Contribute to a Tolerant State

Behavioral opioid tolerance is most often studied in the context of analgesia and cellular signaling mechanisms, as reviewed above. However, opponent processes are also evident at a circuit-level in the regulation of mood and affect. In this section we will focus on how chronic opioid exposure causes adaptations of the mesocorticolimbic circuitry as a result of the development of opponent processes in the striatum and ventral tegmental area (VTA). The striatum is an important hub of the opioid

Allostatic Processes in the VTA

Dopamine release from VTA dopaminergic neurons reinforces natural rewarding behavior and attributes motivational salience to otherwise neutral environmental stimuli or unanticipated salient stimuli 34, 37, 38. Dopaminergic neurons from the VTA exhibit a rich and complex organization, with widespread projections to forebrain targets 39, 40, 41, 42, 43. The rewarding effects of morphine are mediated via activation of MOP because mice lacking this receptor do not express conditioned place

Allostatic Processes in Striatal Cells, Signaling, and Circuits

Similarly to other drugs of abuse, chronic morphine induces extensive and region-specific synaptic plasticity within the striatum. Glutamate homeostasis is affected by changes in glutamate release and reuptake, and in the composition, number, and role of ionotropic and metabotropic receptors ([72] for review). At the level of the synapse, a 10 day period of withdrawal from chronic non-contingent (i.e., experimenter-delivered) morphine increased synaptic strength, as assessed by the ratio of

Opioid-Mediated Aversion Circuitry

The negative affect and ‘anti-reward’ that is created by an opioid-dependent state is now recognized as a driving contributor to drug-seeking behaviors 85, 86, 87, and the neurocircuitry of the learned association between drug-induced relief of these aversive states may be particularly important for opioid substance-abuse disorder. Repeated or chronic use of opioids induces adaptive or allostatic changes that modify neuronal circuitry and create an altered normality – the ‘drug-dependent’ state

Concluding Remarks and Future Directions

Tolerance to opioids per se is not a reliable predictor of abuse liability but presents a challenge for treating both acute and chronic pain, and becomes a liability for addicts that relapse. Opioid tolerance is also a predictor of significantly longer length of hospital stay and readmission rates. Tolerance often masks opioid-induced hyperalgesia and contributes to the development of affective disorders such as anxiety and depression, where the emergence of anxiety during withdrawal can be

Acknowledgments

Financial support was provided by the Shirley and Stefan Hatos Foundation (C.J.E., A.M.W.T., W.W)., Shirley Hatos (C.M.C.), Cousins Center for Psychoneuroimmunology (AMWT), National Institutes of Health (NIH) K99DA040016 (A.M.W.T.), NIH DA005010 (C.J.E., A.M.W.T., W.W.), NIH DA031243 (A.A.A.P.), Department of Defense MR141282 (C.M.C.), and the University of Illinois at Chicago Department of Psychiatry (A.A.A.P.).

Glossary

Allostasis: adaptive modifications of the nervous system following chronic opioid use that create a new stable state dependent on presence of the drug.
Brain-derived neurotrophic factor (BDNF): factor released from neurons and/or microglia that has been shown to contribute to neuronal plasticity during development and pathology, including chronic opioid exposure.
Long-term depression (LTD): an activity-dependent decrease in the strength (or efficacy) of a neuronal synapse that can last for hours or

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Citation Excerpt :
As with TNFα and IL-1β, evidence also suggests that BDNF inhibits the rewarding effects of opioids. As mentioned earlier, elevated levels of BDNF disrupts chloride ion homeostasis in such a way that GABAergic activity is increased (Cahill et al., 2016; Ferrini et al., 2013; Koo et al., 2012; Taylor et al., 2016; Vargas-Perez et al., 2009, 2014). Importantly, it has been shown that opioid-dependent rats have increased levels of BDNF in the VTA (150 % greater than in controls) (Vargas-Perez et al., 2009).
Opioid-induced microglia reactivity affects opioid reward and analgesic processes in ways that may contribute to the neurocognitive impairment observed in opioid addicted individuals. Opioids elicit microglia reactivity through the actions of opioid metabolites at TLR4 receptors, that are located primarily on microglia but are also present on astrocytes. Specifically, the M3G metabolite, which has no affinity for opioid receptors, exerts off-target effects on TLR4 receptors that can trigger downstream immunologic consequences. This off-target microglial reactivity, and the subsequent increase in microglial release of TNFα, IL-1β, and BDNF, have been suggested to modulate both opioid-induced reward and opioid-induced analgesia. Despite occurring independently of each other, these neuro-immune effects could converge and result in overactivation of the insula. This would produce an imbalance between the “impulsive system” and the “executive system”, such that the impulsive system’s influence over behavior becomes dominant. This state, derived from changes in microglial reactivity, could contribute to impairment in a range of neurocognitive domains that are intricately involved in addiction and lead to increases in addiction-related behaviors.

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Trends in Pharmacological Sciences

ReviewAllostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation

Trends

Section snippets

What is Tolerance?

Cellular Allostasis and the Opioid Receptor Signalosome (MOP and DOP)

The Complex Role of Arrestins in Behavioral Tolerance to Opioids

Opponent Processes Contribute to a Tolerant State

Allostatic Processes in the VTA

Allostatic Processes in Striatal Cells, Signaling, and Circuits

Opioid-Mediated Aversion Circuitry

Concluding Remarks and Future Directions

Acknowledgments

Glossary

J. Pain

Brain Res.

Biol. Psychiatry

Neuropharmacology

Eur. J. Pharmacol.

Cell Signal

Cell Rep.

J. Biol. Chem.

J. Biol. Chem.

Pain

Neuron

Brain Res. Brain Res. Rev.

Neuron

Trends Neurosci.

Neuron

Pharmacol. Biochem. Behav.

Behav. Brain Res.

Cell Rep.

Neuron

Brain Res. Bull.

Neuroscience

Neuropharmacology

Neuropharmacology

Curr. Opin. Neurobiol.

Neuron

Pharmacol. Biochem. Behav.

Brain Res.

Opioid tolerance – a predictor of increased length of stay and higher readmission rates

Pain Physician

Opioid abuse in chronic pain – misconceptions and mitigation strategies

N. Engl. J. Med.

Heroin ‘overdose’ death: contribution of drug-associated environmental cues

Science

Delta and kappa opioid receptors as suitable drug targets for pain

Clin. J. Pain

Molecular pharmacology of delta-opioid receptors

Pharmacol. Rev.

Delta-opioid receptors as targets for migraine therapy

Curr. Opin. Neurol.

Kappa antagonist JDTic in Phase 1 clinical trial

Neuropsychopharmacology

Nociceptin/orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems

Pharmacol. Rev.

Ligand-directed signalling within the opioid receptor family

Br. J. Pharmacol.

Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance

Pharmacol. Rev.

Molecular mechanisms of opioid receptor-dependent signaling and behavior

Anesthesiology

Transducing neuronal activity into dendritic spine morphology: new roles for p38 MAP kinase and N-cadherin

Neuroscientist

Opiate-induced molecular and cellular plasticity of ventral tegmental area and locus coeruleus catecholamine neurons

Cold Spring Harb. Perspect. Med.

A novel noncanonical signaling pathway for the mu-opioid receptor

Mol. Pharmacol.

Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence

Nature

Agonist-specific recruitment of arrestin isoforms differentially modify delta opioid receptor function

J. Neurosci.

Differential tolerance to antinociceptive effects of mu opioids during repeated treatment with etonitazene, morphine, or buprenorphine in rats

Psychopharmacology

Ligand-directed trafficking of the delta-opioid receptor in vivo: two paths toward analgesic tolerance

J. Neurosci.

Serine 363 of the δ-opioid receptor is crucial for adopting distinct pathways to activate ERK1/2 in response to stimulation with different ligands

J. Cell Sci.

Evidence that behavioral phenotypes of morphine in beta-arr2-/- mice are due to the unmasking of JNK signaling

Review
Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation