Mu opioid receptor in microglia contributes to morphine analgesic tolerance, hyperalgesia, and withdrawal in mice

Reiss, David J; Maduna, Tando; Maurin, Hervé; Audouard, Emilie; Gavériaux‐Ruff, Claire

doi:10.1002/jnr.24626

Cited by 42 publications

(38 citation statements)

References 89 publications

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“…Consistent with these results, multiple studies have shown that morphine does not induce microglial proinflammatory cytokines in vitro (El-Hage et al 2006;Turchan-Cholewo et al 2009), and morphine alone has no effect on NF-kB, a precursor to microglial activation and production of proinflammatory cytokines (Gessi et al 2016), suggesting that specifically hippocampal microglia may not play a major role in opiate dependence and withdrawal. However, there is extensive literature on the interaction between microglia and opioid dependence and withdrawal that shows microglia, particularly in the spinal cord, is involved in regulating multiple cytokines and drugseeking behaviors (Bland et al 2009;Grace et al 2016;Hutchinson et al 2009;Reiss et al 2020). It would be interesting to determine whether chronic escalating heroin administration can be employed to study heroin withdrawal-induced changes in microglia in the spinal cord both across heroin administration and during withdrawal.…”

Section: Discussionmentioning

confidence: 99%

Dorsal hippocampal interleukin-1 signaling mediates heroin withdrawal-enhanced fear learning

et al. 2020

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Converging evidence suggests opioid abuse can increase the incidence and severity of post-traumatic stress disorder (PTSD) in clinical populations. Interestingly, opioid withdrawal alone can produce symptoms similar to those of PTSD. Despite this association, the neural mechanisms underlying the relationship of opioid abuse, withdrawal, and PTSD is poorly understood. Our laboratory has investigated the neurobiological underpinnings of stress-enhanced fear learning (SEFL), an animal model of PTSD-like symptoms. We have previously shown that, in SEFL, a severe footshock induces an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β), and subsequent fear learning is blocked by DH IL-1 receptor antagonism (IL-1RA). Given that opioids and stress engage similar neuroimmune mechanisms, the present experiments investigate whether the same mechanisms drive heroin withdrawal to induce a PTSD-like phenotype. First, we tested the effect of a chronic escalating heroin dose and withdrawal regimen on fear learning and found it produces enhanced future fear learning. Heroin withdrawal also induces a timedependent, region-specific increase in IL-1β and glial fibrillary acidic protein (GFAP) immunoreactivity within the dentate gyrus of the DH. IL-1β was significantly colocalized with GFAP, indicating astrocytes may be involved in increased IL-1β. Moreover, intra-DH infusions of IL-1RA 0, 24, and 48 h into heroin withdrawal prevents the development of enhanced fear learning but does not alter withdrawal-induced weight loss. Collectively, our data suggests heroin withdrawal is sufficient to produce enhanced fear learning, astrocytes may play a role in heroin withdrawal-induced IL-1β, and DH IL-1 signaling during withdrawal mediates the development of heroin withdrawal-enhanced fear learning.

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Section: Discussionmentioning

confidence: 99%

Dorsal hippocampal interleukin-1 signaling mediates heroin withdrawal-enhanced fear learning

et al. 2020

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“…This suggests that astrocytic DOR contributes to DOR-mediated tolerance in females. Recently, we have shown that MOR deletion in microglia delayed analgesic tolerance to morphine, indicating a role for microglial MOR in this morphine chronic effect (Reiss et al, 2020 ). Also, astrocytic MOR activity was shown to be involved in MOR-dependent long-term potentiation in the hippocampus and in morphine-induced conditioned place preference, although tolerance was not studied (Nam et al, 2019 ).…”

Section: Discussionmentioning

confidence: 93%

“…The numbers of males and females of each genotype from each brain area were as follows: dorsal root ganglia, DOR-flox, n = 4 males, n = 6 females; GFAP-DOR-KO, n = 5 males, n = 7 females; spinal cord, DOR-flox, n = 5 males, n = 5 females; GFAP-DOR-KO, n = 5 males, n = 8 females; olfactory bulb, DOR-flox, n = 4 males, n = 6 females; GFAP-DOR-KO, n = 5 males, n = 7 females; cortex, DOR-flox, n = 6 males, n = 9 females; GFAP-DOR-KO, n = 4 males, n = 5 females; hippocampus, DOR-flox, n = 6 males, n = 7 females; GFAP-DOR-KO, n = 4 males, n = 6 females; caudate putamen, DOR-flox, n = 6 males, n = 6 females; GFAP-DOR-KO, n = 4 males, n = 3 females; periacqueductal gray, DOR-flox, n = 12 males, n = 5 females; GFAP-DOR-KO, n = 9 males, n = 4 females; brainstem, DOR-flox, n = 6 males, n = 8 females; GFAP-DOR-KO, n = 7 males, n = 6 females. Quantitative RT-PCR was performed on tissues and isolated astrocyte RNA as described (Reiss et al, 2020 ). Briefly, total RNA was extracted with a Nucleospin kit (Macherey Nagel, Hoerdt, France) and precipitated overnight with acetate/ethanol.…”

Section: Methodsmentioning

confidence: 99%

Delta Opioid Receptor in Astrocytes Contributes to Neuropathic Cold Pain and Analgesic Tolerance in Female Mice

Reiss

Maurin

Audouard

et al. 2021

Front. Cell. Neurosci.

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Background: The delta opioid receptor (DOR) contributes to pain control, and a major challenge is the identification of DOR populations that control pain, analgesia, and tolerance. Astrocytes are known as important cells in the pathophysiology of chronic pain, and many studies report an increased prevalence of pain in women. However, the implication of astrocytic DOR in neuropathic pain and analgesia, as well as the influence of sex in this receptor activity, remains unknown.Experimental Approach: We developed a novel conditional knockout (cKO) mouse line wherein DOR is deleted in astrocytes (named GFAP-DOR-KO), and investigated neuropathic mechanical allodynia as well as analgesia and analgesic tolerance in mutant male and female mice. Neuropathic cold allodynia was also characterized in mice of both sexes lacking DOR either in astrocytes or constitutively.Results: Neuropathic mechanical allodynia was similar in GFAP-DOR-KO and floxed DOR control mice, and the DOR agonist SNC80 produced analgesia in mutant mice of both sexes. Interestingly, analgesic tolerance developed in cKO males and was abolished in cKO females. Cold neuropathic allodynia was reduced in mice with decreased DOR in astrocytes. By contrast, cold allodynia was exacerbated in full DOR KO females.Conclusions: These findings show that astrocytic DOR has a prominent role in promoting cold allodynia and analgesic tolerance in females, while overall DOR activity was protective. Altogether this suggests that endogenous- and exogenous-mediated DOR activity in astrocytes worsens neuropathic allodynia while DOR activity in other cells attenuates this form of pain. In conclusion, our results show a sex-specific implication of astrocytic DOR in neuropathic pain and analgesic tolerance. These findings open new avenues for developing tailored DOR-mediated analgesic strategies.

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“…Hence, it is critical to use complementary strategies of microglial manipulations. CD11b-Cre-driven CKO of BDNF and Cx3cr1-Cre-driven CKO of MOR were reported to impair thermal OIH [17; 33]. However, because CD11b and Cx3cr1 are also expressed in multiple other cell types in addition to microglia [24; 27; 31], the possibility that the CKOs in non-microglial cells caused the observed impairment of thermal OIH in mutant mice has not been conclusively excluded.…”

Section: Discussionmentioning

confidence: 99%

“…Selective inhibition by minocycline or by anti-MAC1 (CD11B)-saporin impaired the expression of thermal hyperalgesia induced by morphine[17; 20]. Conditional knockout (CKO) of BDNF induced by CD11b-Cre and CKO of Mu opioid receptor (MOR) driven by Cx3cr1-Cre were reported to impair thermal OIH[17; 33]. It was also reported that opioids simulated microglia via Toll-like receptor 4 (TLR4) [21], and activated microglia may promote OIH expression by releasing signaling molecules such as cytokines, BDNF and ATP[35].…”

Section: Introductionmentioning

confidence: 99%

Microglial ablation does not affect opioid-induced hyperalgesia in rodents

Liu

Yang

et al. 2021

Preprint

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Opioids are the frontline analgesics in pain management. However, chronic use of opioid analgesics causes paradoxical pain that contributes to the decrease of their efficacy in pain control and the escalation of dose in long-term management of pain. The underling pathogenic mechanism is not well understood. Microglia have been commonly thought to play a critical role in the expression of opioid-induced hyperalgesia (OIH) in animal models. We performed microglial ablation experiments using either a genetic (CD11b-diphtheria toxin receptor transgenic mouse) or pharmacological (colony-stimulating factor 1 receptor inhibitor PLX5622) approaches. Surprisingly, ablating microglia using these specific and effective approaches did not cause detectable impairment in the expression of hyperalgesia induced by morphine. We confirmed this conclusion with behavioral test of mechanical and thermal hyperalgesia, in male and female mice, and with different species (mouse and rat). These findings raise caution about the widely assumed contribution of microglia to the development of OIH.

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Mu opioid receptor in microglia contributes to morphine analgesic tolerance, hyperalgesia, and withdrawal in mice

Cited by 42 publications

References 89 publications

Dorsal hippocampal interleukin-1 signaling mediates heroin withdrawal-enhanced fear learning

Dorsal hippocampal interleukin-1 signaling mediates heroin withdrawal-enhanced fear learning

Delta Opioid Receptor in Astrocytes Contributes to Neuropathic Cold Pain and Analgesic Tolerance in Female Mice

Microglial ablation does not affect opioid-induced hyperalgesia in rodents

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