Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4

Bachtell, Ryan K.; Hutchinson, Mark R.; Wang, Xiaohui; Rice, Kenner C.; Maier, Steven F.; Watkins, Linda R.

doi:10.2174/1871527314666150529132503

Cited by 80 publications

(49 citation statements)

References 69 publications

(93 reference statements)

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“…Therapeutics targeting TLRs certainly offers a promising avenue for investigation, given their involvement across many classes of drugs. For a discussion on the translational potential of TLR4 antagonism in the context of drug abuse, see Bachtell et al (2015). Alternatively, methods for manipulating anti-inflammatory cytokines such as IL-10 may yield some promise for treating drug-induced inflammation.…”

Section: Future Research Directions and Clinical Implicationsmentioning

confidence: 99%

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Lacagnina

Rivera

Bilbo

2016

Neuropsychopharmacol

218

170

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Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders.

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Section: Future Research Directions and Clinical Implicationsmentioning

confidence: 99%

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Lacagnina

Rivera

Bilbo

2016

Neuropsychopharmacol

218

170

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“…Further, place conditioning and elevations in dopamine (DA) levels in the nucleus accumbens shell (NAS) produced by opioids and cocaine were reported to be blunted by (+)-naltrexone and (+)-naloxone (Hutchinson et al, 2012;Northcutt et al, 2015). Together, these findings suggest a role for TLR4 in drug dependence to both opioids and psychostimulants, as well as an approach to the development of treatments for substance abuse disorders (Bachtell et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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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“…(+)-naloxone and (+)-naltrexone have well-described antagonist effects at the toll-like receptor 4 (TLR4), which may also contribute to the abuse-related effects of cocaine or opioid agonists (Bachtell et al 2015;Hutchinson et al 2012;Tanda et al 2016;Yue et al 2020), so it would be interesting to test whether the structurally similar (+)-IBNtxA may also have TLR4 effects.…”

Section: Discussionmentioning

confidence: 99%

Abuse liability, antinociceptive, and discriminative stimulus properties of IBNtxA

Islam¹,

Rahman²,

Brenner³

et al. 2020

Preprint

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Rationale: IBNtxA (3-iodobenzoyl naltrexamine) is a novel μ opioid receptor (MOR) agonist structurally related to the classical MOR antagonist naltrexone. Recent studies suggest IBNtxA preferentially signals through truncated MOR splice variants, producing a unique pharmacological profile resulting in antinociception with reduced side effects, including no conditioned place preference (CPP) when tested at a single dose. IBNtxA represents an intriguing lead compound for preclinical drug development targeting truncated MOR splice variants but further evaluation of its in vivo pharmacological profile is necessary to evaluate its potential.Objective: The purpose of this study was to independently verify the antinociceptive properties of IBNtxA and to more completely examine the rewarding properties and discriminative stimulus effects of IBNtxA. These results will allow broader assessment of IBNtxA as a translational candidate or lead compound for further development.Results: IBNtxA was synthesized and compared to morphine in a variety of mouse behavioral assays. 3 mg/kg IBNtxA was equipotent to 10 mg/kg morphine in a hot plate analgesia assay. In drug discrimination testing using mice trained to discriminate between 3 mg/kg IBNtxA and DMSO/saline vehicle, the κ agonist U-50488 fully substituted for IBNtxA. Classical μ agonist morphine, δ agonist SNC162, NOP agonist SCH 221510, and μ/NOP partial agonist buprenorphine each partially substituted for IBNtxA. IBNtxA up to 3 mg/kg did not produce a place preference in CPP. Pretreatment with 3 mg/kg IBNtxA but not 1 mg/kg IBNtxA attenuated acquisition of place preference for 10 mg/kg morphine. 3 mg/kg IBNtxA attenuated morphine-induced hyperlocomotion but did not alter naloxone-precipitated morphine withdrawal. Conclusions:Overall IBNtxA has a complicated opioid receptor pharmacology in vivo. These results indicate that IBNtxA produces potent antinociception and has low abuse liability, likely driven by substantial κ agonist signaling effects.

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Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4

Cited by 80 publications

References 69 publications

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

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

Abuse liability, antinociceptive, and discriminative stimulus properties of IBNtxA

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