Microglial activation involved in morphine tolerance is not mediated by toll-like receptor 4

Fukagawa, Hiroshi; Koyama, Tomohiro; Kakuyama, Masahiro; Fukuda, Kazuhiko

doi:10.1007/s00540-012-1469-4

Cited by 69 publications

(54 citation statements)

References 14 publications

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“…However, a recent study by Fukagawa and colleagues [39] reported a dissociation between TLR4 and opioid tolerance; they found that morphine tolerance develops in the absence of TLR4. Here, we examined the link between TLR4 and opioid analgesia in two inbred mouse strains: C3H/HeJ mice which have a dominant-negative point mutation in the Tlr4 gene, and B10ScNJ mice which are null mutants for TLR4.…”

Section: Discussionmentioning

confidence: 96%

Toll-Like Receptor 4 Mutant and Null Mice Retain Morphine-Induced Tolerance, Hyperalgesia, and Physical Dependence

et al. 2014

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The innate immune system modulates opioid-induced effects within the central nervous system and one target that has received considerable attention is the toll-like receptor 4 (TLR4). Here, we examined the contribution of TLR4 in the development of morphine tolerance, hyperalgesia, and physical dependence in two inbred mouse strains: C3H/HeJ mice which have a dominant negative point mutation in the Tlr4 gene rendering the receptor non-functional, and B10ScNJ mice which are TLR4 null mutants. We found that neither acute antinociceptive response to a single dose of morphine, nor the development of analgesic tolerance to repeated morphine treatment, was affected by TLR4 genotype. Likewise, opioid induced hyperalgesia and opioid physical dependence (assessed by naloxone precipitated withdrawal) were not altered in TLR4 mutant or null mice. We also examined the behavioural consequence of two stereoisomers of naloxone: (−) naloxone, an opioid receptor antagonist, and (+) naloxone, a purported antagonist of TLR4. Both stereoisomers of naloxone suppressed opioid induced hyperalgesia in wild-type control, TLR4 mutant, and TLR4 null mice. Collectively, our data suggest that TLR4 is not required for opioid-induced analgesic tolerance, hyperalgesia, or physical dependence.

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Section: Discussionmentioning

confidence: 96%

Toll-Like Receptor 4 Mutant and Null Mice Retain Morphine-Induced Tolerance, Hyperalgesia, and Physical Dependence

et al. 2014

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“…There are many hypotheses about how opioid tolerance develops, including, functional decoupling of opioid receptors from G-proteins which leads to receptor desensitization, phosphorylation of opioid receptors, internalization and/or down-regulation of μ-opioid receptor, upregulation of the cAMP (cyclic adenosine monophosphate) and PKC (protein kinase C) pathways, neuroimmune activation and neuroinflammation, glutamate homeostasis, nitric oxide production, modulatory role of ion channels or neurotrophic factors and activation of glial cells (astrocytes and microglia) at the level of the spinal cord (Ben-Eliyahu et al, 1992;Bian et al, 2012;Dang and Christie, 2012;DeLeo et al, 2004;Fukagawa et al, 2013;Koch and Höllt, 2008;Kolesnikov et al, 1993;Martini and Whistler, 2007;Ossipov et al, 2004;Vacca et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin attenuates the antinociceptive tolerance of morphine via nitric oxide dependent pathway in male mice

Hassanipour

Amini-Khoei

Shafaroodi

et al. 2016

Brain Research Bulletin

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“…However, there are several other findings that may temper the promise of reported interactions among TLR4 antagonists and abused drugs. In particular, recent studies have not confirmed involvement of TLR4 in morphine-induced tolerance or dependence (Fukagawa et al, 2013;Skolnick et al, 2014;Stevens et al, 2013) or the attenuation of tolerance produced by the microglial inhibition (Fukagawa et al, 2013). Further, a recent paper (Mattioli et al, 2014) demonstrated with in vivo studies that morphine-induced tolerance, hyperalgesia and physiological dependence was retained in TLR4 genetically modified null mice.…”

Section: Introductionmentioning

confidence: 95%

Lack of Specific Involvement of (+)-Naloxone and (+)-Naltrexone on the Reinforcing and Neurochemical Effects of Cocaine and Opioids

Tanda

Mereu

Hiranita

et al. 2016

Neuropsychopharmacol

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Effective medications for drug abuse remain a largely unmet goal in biomedical science. Recently, the (+)-enantiomers of naloxone and naltrexone, TLR4 antagonists, have been reported to attenuate preclinical indicators of both opioid and stimulant abuse. To further examine the potential of these compounds as drug-abuse treatments, we extended the previous assessments to include a wider range of doses and procedures. We report the assessment of (+)-naloxone and (+)-naltrexone on the acute dopaminergic effects of cocaine and heroin determined by in vivo microdialysis, on the reinforcing effects of cocaine and the opioid agonist, remifentanil, tested under intravenous self-administration procedures, as well as the subjective effects of cocaine determined by discriminative-stimulus effects in rats. Pretreatments with (+)-naloxone or (+)-naltrexone did not attenuate, and under certain conditions enhanced the stimulation of dopamine levels produced by cocaine or heroin in the nucleus accumbens shell. Furthermore, although an attenuation of either cocaine or remifentanil self-administration was obtained at the highest doses of (+)-naloxone and (+)-naltrexone, those doses also attenuated rates of food-maintained behaviors, indicating a lack of selectivity of TLR4 antagonist effects for behaviors reinforced with drug injections. Drug-discrimination studies failed to demonstrate a significant interaction of (+)-naloxone with subjective effects of cocaine. The present studies demonstrate that under a wide range of doses and experimental conditions, the TLR4 antagonists, (+)-naloxone and (+)-naltrexone, did not specifically block neurochemical or behavioral abuse-related effects of cocaine or opioid agonists.

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Microglial activation involved in morphine tolerance is not mediated by toll-like receptor 4

Abstract: Microglial activation caused by a mechanism independent of TLR4 is involved in the development of morphine tolerance. Further studies are necessary to clarify the cellular mechanisms of morphine-induced microglial activation.

Cited by 69 publications

References 14 publications

Toll-Like Receptor 4 Mutant and Null Mice Retain Morphine-Induced Tolerance, Hyperalgesia, and Physical Dependence

Toll-Like Receptor 4 Mutant and Null Mice Retain Morphine-Induced Tolerance, Hyperalgesia, and Physical Dependence

Atorvastatin attenuates the antinociceptive tolerance of morphine via nitric oxide dependent pathway in male mice

Lack of Specific Involvement of (+)-Naloxone and (+)-Naltrexone on the Reinforcing and Neurochemical Effects of Cocaine and Opioids

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