Allostatic mechanisms of opioid tolerance beyond desensitization and downregulation
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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.
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Acute opioid effects activate G proteins through the mu-opioid receptor and modulate second messengers and cellular effectors that generate short-term and long-term neuroadaptations relevant to a blunted hedonic response to the drug (tolerance).
“For the acute effects of opioid drugs, G proteins are activated through the m-opioid receptor and modulate the activity of several second messengers and cellular effectors that generate both short-term and long-term neuroadaptations that are relevant to a blunted hedonic response to the drug (i.e., tolerance; Cahill et al., 2016).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Cahill et al., 2016
Microglia via a BDNF-potassium-chloride transporter member 5 mechanism are activated during opioid withdrawal and increase VTA GABAergic tone, which inhibits dopaminergic neurons.
“Here, microglia via a BDNF-potassium-chloride transporter member 5 mechanism are hypothesized to be activated during opioid withdrawal and increase VTA GABAergic tone, which inhibits dopaminergic neurons (Cahill et al., 2016).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Cahill et al., 2016
Acute opioid administration exerts anti-inflammatory effects, whereas chronic opioid exposure activates microglia and astrocytes in the spinal cord and central nervous system, including the VTA, NAc, frontal cortex, and periaqueductal gray.
“The acute administration of opioids exerts anti-inflammatory effects (Eisenstein, 2019), whereas chronic opioid exposure activates microglia and astrocytes in the spinal cord (Watkins et al., 2009;Cahill et al., 2016) and central nervous system, including the VTA, NAc, frontal cortex, and periaqueductal gray (Hao et al., 2011;Taylor et al., 2016).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Cahill et al., 2016
Cahill et al. is cited for the spinal-cord portion of the sentence, not the acute anti-inflammatory effect or the other named brain regions. The 'Allostatic Processes in the VTA' section discusses activated microglia after prolonged morphine exposure, and the References list includes work on spinal astrocytes, but the passages found do not state that chronic opioid exposure activates both microglia and astrocytes in the spinal cord (searched: spinal cord, glial activation, microglia and astrocytes). (LLM, conf=0.72)
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Neurobiology of opioid addiction: Opponent process, hyperkatifeia, and negative reinforcement
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- Authors
- Cahill, C. M., Walwyn, W., Taylor, A. M. W., Pradhan, A. A. A., & Evans, C. J.
- Affiliations
- University of California, Irvine (US)
- University of California, Los Angeles (US)
- University of Illinois Chicago (US)
- Corresponding author
- Evans, Christopher J.
- Venue
- Trends in Pharmacological Sciences
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 37
- Issue
- 11
- Pages
- 963-976
- ISSN
- 0165-6147 (ISSN-L)
- PMC
- PMC5240843
- OpenAlex
- W2523270510
- Cited by
- 122
- References
- 128
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 9 · 2023: 14 · 2022: 11 · 2021: 15 · 2020: 19 · 2019: 15 · 2018: 15 · 2017: 11
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Trends in Pharmacological Sciences (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Shirley and Stefan Hatos Foundation
- Cousins Center for Psychoneuroimmunology
- National Institutes of Health (K99DA040016, NIH DA005010, NIH DA031243)
- Department of Defense (MR141282)
- University of Illinois at Chicago Department of Psychiatry
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- opioid tolerance, mu-opioid receptor, delta opioid receptor, behavioral tolerance, analgesic tolerance, microglia, receptor desensitization, receptor down-regulation
- MeSH terms
- Analgesics, Opioid, Animals, Brain, Drug Tolerance, Humans, Receptors, Opioid, Down-Regulation, Receptors, Opioid, mu, Receptors, Opioid, delta, Allostasis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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