Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation

Ballester, Javier; Baker, Anne K.; Martikainen, Ilkka K.; Koppelmans, Vincent; Zubieta, Jon-Kar; Love, Tiffany M.

doi:10.1038/s41398-021-01775-z

Cited by 5 publications

(3 citation statements)

References 70 publications

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“…For example, rats with sciatic nerve ligation exhibit reduced placed preference induced by intra-VTA administration of the MOPR agonist, DAMGO, or systemic administration of morphine-an effect paralleled by attenuated MOPR binding in the VTA (Niikura et al, 2008). Consistent with this idea, chronic pain patients at low risk for opioid misuse exhibit less pain-induced activation of MOPR in the NAc, and this effect is associated with fewer mood disturbances and negative affect (Ballester et al, 2022).…”

Section: Opioidsmentioning

confidence: 90%

Endogenous opioid systems alterations in pain and opioid use disorder

Higginbotham

Markovic

Massaly

et al. 2022

Front. Syst. Neurosci.

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Decades of research advances have established a central role for endogenous opioid systems in regulating reward processing, mood, motivation, learning and memory, gastrointestinal function, and pain relief. Endogenous opioid systems are present ubiquitously throughout the central and peripheral nervous system. They are composed of four families, namely the μ (MOPR), κ (KOPR), δ (DOPR), and nociceptin/orphanin FQ (NOPR) opioid receptors systems. These receptors signal through the action of their endogenous opioid peptides β-endorphins, dynorphins, enkephalins, and nociceptins, respectfully, to maintain homeostasis under normal physiological states. Due to their prominent role in pain regulation, exogenous opioids—primarily targeting the MOPR, have been historically used in medicine as analgesics, but their ability to produce euphoric effects also present high risks for abuse. The ability of pain and opioid use to perturb endogenous opioid system function, particularly within the central nervous system, may increase the likelihood of developing opioid use disorder (OUD). Today, the opioid crisis represents a major social, economic, and public health concern. In this review, we summarize the current state of the literature on the function, expression, pharmacology, and regulation of endogenous opioid systems in pain. Additionally, we discuss the adaptations in the endogenous opioid systems upon use of exogenous opioids which contribute to the development of OUD. Finally, we describe the intricate relationship between pain, endogenous opioid systems, and the proclivity for opioid misuse, as well as potential advances in generating safer and more efficient pain therapies.

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Section: Opioidsmentioning

confidence: 90%

Endogenous opioid systems alterations in pain and opioid use disorder

Higginbotham

Markovic

Massaly

et al. 2022

Front. Syst. Neurosci.

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“…This locus has been associated with the antinociceptive effect of morphine (Bergeson et al, 2001). Oprm1 encodes the primary receptor responsible for morphine induced locomotor response (Severino et al, 2020; Smith et al, 2009), and is also responsible for its addiction liability (Ballester et al, 2022; Zhang et al, 2020). Morphine-induced locomotion was affected by Oprm1 variants (Popova et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Opiate responses are controlled by interactions ofOprm1andFgf12loci in rodents: Correspondence to human GWAS findings

Lemen

Zuo²,

Hatoum

et al. 2022

Preprint

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We analyzed time dependent behavioral responses to morphine and naloxone obtained from a large family of young adult BXD mice (n = 70 strains, including C57BL/6J and DBA/2J parents, 4 to 9 cases per strain) using the latest whole genome sequencing (WGS)-based genetic markers. These data include quantitative locomotor and behavior responses measured three hours after an acute morphine injection (50 mg/kg i.p.), followed by naloxone-induced withdrawal, obtained by Philip et al (2010). Locomotor data were analyzed in 15 min bins and mapped jointly for both sexes or independently for males and females. We confirmed a highly significant association between locomotor response and a genomic region that overlaps with Oprm1 on Chr 10 at 6.8 Mb (LOD maximum of 11.4) between 15-105 min, with a peak at 75 min. Effects were modestly dependent of sex. Strains that were B homozygotes run 76 meters farther than those that are D homozygotes after a morphine injection. We discovered a novel association between a locus on Chr 16 and a late phase locomotor response (after 150 min) in both sexes. This locus had a significant but transient epistatic interaction with the Oprm1 locus between 45-90 min, well before the main effect was detectable. The Chr 16 locus includes one compelling candidate fibroblast growth factor 12 (Fgf12). Null mutation of Fgf12 has been shown to cause locomotor deficits (e.g., ataxia) in mice. Analysis of genes correlated with both OPRM1 and FGF12 in six human brain regions (GTEx, v8) demonstrated an enrichment of genetic signals associated with SUD phenotypes, and a modest corroboration of variants in the FGF12 loci on Chr 3q28. To the best of our knowledge this is the first demonstration of a transient time dependent epistatic interaction modulating drug response in mammals; a finding with interesting mechanistic implications. Finally, this work demonstrates how high-quality FAIR+ data can be used with newly acquired data sets to yield striking results, and how joint mouse and human neurogenomic and mapping data can be merged at gene and network levels for bidirectional validation of potential SUD variants and molecular networks.

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“…The endogenous mu-opioid system is reported to be disrupted in a range of mental and physical health conditions, notably chronic pain with (Ballester et al, 2022) and without chronic opioid treatment (Harris et al, 2007;Martikainen et al, 2013;Thompson et al, 2018;Willoch et al, 2004), alcohol (Heinz et al, 2004;Hermann et al, 2017;Weerts et al, 2011) and substance use disorder (Colasanti et al, 2013;Gorelick et al, 2005;Williams et al, 2009), behavioural addictions (Majuri et al, 2016;Mick et al, 2016), schizophrenia (Ashok et al, 2019) and Parkinson's dyskinesia (Piccini et al, 1997). Disruptions in endogenous mu-opioid signalling could disturb behaviours important for forming and maintaining social connection and thereby contribute to disability in these populations.…”

Section: Introductionmentioning

confidence: 99%

Endogenous Mu-Opioid Modulation of Social Connection in Humans: A Systematic Review and Meta-Analysis

Løseth,

Trøstheim,

Leknes

2023

Preprint

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Background: Social bonding, essential for health and survival in all social species, depends on mu-opioid signalling in non-human mammals. A growing neuroimaging and psychopharmacology literature also implicates mu-opioids in human social connectedness. Methods: To determine the role of mu-opioids for social connectedness in healthy humans, we conducted a preregistered (osf.io/x5wmq) multilevel random-effects meta-analysis of randomized double-blind placebo-controlled opioid antagonist studies. We included data from 8 publications and 2 unpublished projects, totalling 17 outcomes (N = 455) sourced from a final literature search in Web of Science, Scopus, PubMed and EMBASE on October 12, 2023, and through community contributions. All studies used naltrexone (25-100mg) to block the mu-opioid system and measured social connectedness by self-report. Results: Opioid antagonism slightly reduced feelings of social connectedness (Hedges’ g [95% CI) = -0.20 [-0.32, -0.07]. Results were highly consistent within and between studies (I2 = 23%). However, there was some indication of bias in favour of larger effects among smaller studies (Egger’s test: B = -2.16, SE = 0.93, z = -2.33, p = 0.02), and publication bias analysis indicated that the effect of naltrexone might be overestimated.Discussion: The results clearly demonstrate that intact mu-opioid signalling is not essential for experiencing social connectedness, as robust feelings of connectedness are evident even during full pharmacological mu-opioid blockade. Nevertheless, antagonism reduced measures of social connection, consistent with a modulatory role of mu-opioids for human social connectedness. The modest effect size relative to findings in non-human animals, could be related to differences in measurement (subjective human responses versus behavioural/motivation indices in animals), species specific neural mechanisms, or naltrexone effects on other opioid receptor subtypes. In sum, these results help explain how mu-opioid dysregulation and social disconnection can contribute to disability, and conversely – how social connection can buffer risk of ill health. Other: This work was supported by the European Research Council.

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Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation

Cited by 5 publications

References 70 publications

Endogenous opioid systems alterations in pain and opioid use disorder

Endogenous opioid systems alterations in pain and opioid use disorder

Opiate responses are controlled by interactions ofOprm1andFgf12loci in rodents: Correspondence to human GWAS findings

Endogenous Mu-Opioid Modulation of Social Connection in Humans: A Systematic Review and Meta-Analysis

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