Cited by 438Pain Mechanisms and TreatmentsPain Management and Opioid UseNeuropeptides and Animal Physiology

The “toll” of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia

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Watkins, Linda R., Hutchinson, Mark R., Rice, Kenner C., Maier, Steven F.·2009·Trends in Pharmacological Sciences

Abstract

Glial activation participates in the mediation of pain including neuropathic pain, due to release of neuroexcitatory, proinflammatory products. Glial activation is now known to occur in response to opioids as well. Opioid-induced glial activation opposes opioid analgesia and enhances opioid tolerance, dependence, reward and respiratory depression. Such effects can occur, not via classical opioid receptors, but rather via non-stereoselective activation of toll-like receptor 4 (TLR4), a recently recognized key glial receptor participating in neuropathic pain as well. This discovery identifies a means for separating the beneficial actions of opioids (opioid receptor mediated) from the unwanted side-effects (TLR4/glial mediated) by pharmacologically targeting TLR4. Such a drug should be a stand-alone therapeutic for treating neuropathic pain as well. Excitingly, with newly-established clinical trials of two glial modulators for treating neuropathic pain and improving the utility of opioids, translation from rats-to-humans now begins with the promise of improved clinical pain control.

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Crossref · 10.1016/j.tips.2009.08.002

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114 of 114 references verified0 citation errors · 0 not checkable

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  • Blockade of glial cell activation restores mesolimbic dopamine function, prevents withdrawal, prevents relapse of morphine-seeking behavior, and prevents incubation-induced heroin seeking in rats.

    “The blockade of glial cell activation restored mesolimbic dopamine function using minocycline (Taylor et al., 2016), prevented withdrawal using various inhibitors of glial cell activation (Watkins et al., 2009), prevented the relapse of morphine-seeking behavior via the epigenetic reprogramming of interleukin-10 overexpression (Schwarz et al., 2011), and prevented incubation-induced heroin seeking”

    From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Watkins et al., 2009

    The Watkins et al. citation is attached only to the withdrawal claim, not the separately cited dopamine or morphine-seeking claims. The References (page unavailable) list a study reporting reduced opioid withdrawal with the glial modulator ibudilast, and the Concluding remarks predict suppression of opioid dependence. Neither establishes that glial-activation inhibitors prevent withdrawal altogether. (LLM, conf=0.85)

    Experimental — accuracy not yet measured
  • 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).”
  • Within the CNS, opioid administration leads to the activation of microglia via a toll-like receptor (TLR)-4-dependent mechanism, and produces paradoxical aggravation of proinflammatory immune responses.

    “Moreover, an overwhelming amount of evidence demonstrates that within the CNS, opioid administration leads to the activation of microglia via a toll-like receptor (TLR)-4-dependent mechanism, and produces paradoxical aggravation of proinflammatory immune responses (Hutchinson et al, 2007;Watkins et al, 2009).”

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1 retracted

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Research works printed but not linked: 3

  1. [45]Hutchinson MR 2009 Novel toll-like receptor 4 activity of opioids: implications for opioid analgesia and dependence Journal of Neuroscience revision in review
  2. [46]Lewis SS 2009 Morphine-3-glucuronide cuases enhance pain through proinflammatory glial mechanisms Neuroscience in review
  3. [73]Lewis SS 2009 Constriction of the facial nerve leads to increased sensitivity to somatosensory and auditory stimuli: characterization of an inflammatory and glial component Proc Soc Neurosci in press

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Authors
Watkins, L. R., Hutchinson, M. R., Rice, K. C., & Maier, S. F.
Affiliations
  • University of Colorado Boulder (US)
  • National Institutes of Health (US)
Corresponding author
Watkins, Linda R.
Venue
Trends in Pharmacological Sciences
Publisher
Elsevier BV
Published
2009-11
Volume
30
Issue
11
Pages
581-591
ISSN
0165-6147 (ISSN-L)
OpenAlex
W2103076324
Cited by
438
References
114
Citations by year
2026: 14 · 2025: 17 · 2024: 8 · 2023: 11 · 2022: 17 · 2021: 72 · 2020: 21 · 2019: 28 · 2018: 32 · 2017: 23 · 2016: 35 · 2015: 26 · 2014: 29 · 2013: 24 · 2012: 30
FWCI
17.95
Type
journal article
Language
en
Open access
Locations
  • Trends in Pharmacological Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
Funders
  • Merck Company Foundation
  • American Australian Association
  • International Association for the Study of Pain
  • National Institutes of Health
  • U.S. Food and Drug Administration
  • National Health and Medical Research Council
  • National Medical Research Council
  • National Institute on Alcohol Abuse and Alcoholism
  • National Institute on Drug Abuse (DA017670, K02DA015642, DA024044, DA 015642, R01DA023132, R01DA017670, K05DA024044)
  • National Institute of Dental and Craniofacial Research (DE017782, R01DE017782)
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
TLR4, neuropathic pain, opioid tolerance, opioid use disorder, respiratory depression, opioid analgesia, neuroinflammation
MeSH terms
Analgesics, Opioid, Animals, Clinical Trials as Topic, Humans, Neuralgia, Neuroglia, Pain, Drug Delivery Systems, Toll-Like Receptor 4, Rats

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