BK channels in microglia are required for morphine-induced hyperalgesia

Hayashi, Yoshinori; Morinaga, Saori; Zhang, Jing; Satoh, Yasushi; Meredith, Andrea L.; Nakata, Takashi; Wu, Zhou; Kohsaka, Shinichi; Inoue, Kazuhide; Nakanishi, Hiroshi

doi:10.1038/ncomms11697

Cited by 60 publications

(69 citation statements)

References 68 publications

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“…Nevertheless, since the abrupt discontinuation of prolonged opioid use can result in a withdrawal syndrome, including enhanced pain, the OIH may in fact represent the opioid withdrawal-induced hyperalgesia [reviewed by (134)]. The majority of studies have focused on the effects of morphine and on MOP receptors, but only a few directly addressed the microglia following chronic morphine treatment, and showed that tolerance and/or OIH were reduced by microglia depletion (105,135) (Figure 1C). The former study proposed that morphine activated MOP receptors on spinal cord microglia to increase the expression of purinergic P2X4 receptors, which triggered the (MOP receptor-independent) release of brainderived neurotrophic factor (BDNF) from microglia.…”

Section: Gliamentioning

confidence: 99%

“…These actions were implied to mediate OIH, but not tolerance (105). Hayashi et al (135) suggested that both tolerance and OIH involved microglia MOP receptor-induced secretion of arachidonic acid (AA) and subsequent activation of microglial large conductance Ca 2+ -activated K + (BK) channels in the spinal cord. Several other studies showed the correlation between tolerance or OIH and the involvement of spinal cord microglia and/or astrocytes in morphine-treated animals.…”

Section: Gliamentioning

confidence: 99%

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Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

2020

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neurons can induce analgesia in animal models, but the most clinically relevant are MOP receptor agonists (e.g., morphine, fentanyl). Opioids can also affect the function of immune cells, and their actions in relation to immunosuppression and infections have been widely discussed. Here, we analyze the expression and the role of opioid receptors in peripheral immune cells and glia in the modulation of pain. All four opioid receptors have been identified at the mRNA and protein levels in immune cells (lymphocytes, granulocytes, monocytes, macrophages) in humans, rhesus monkeys, rats or mice. Activation of leukocyte MOP, DOP, and KOP receptors was recently reported to attenuate pain after nerve injury in mice. This involved intracellular Ca 2+ -regulated release of opioid peptides from immune cells, which subsequently activated MOP, DOP, and KOP receptors on peripheral neurons. There is no evidence of pain modulation by leukocyte NOP receptors. More good quality studies are needed to verify the presence of DOP, KOP, and NOP receptors in native glia. Although still questioned, MOP receptors might be expressed in brain or spinal cord microglia and astrocytes in humans, mice, and rats. Morphine acting at spinal cord microglia is often reported to induce hyperalgesia in rodents. However, most studies used animals without pathological pain and/or unconventional paradigms (e.g., high or ultra-low doses, pain assessment after abrupt discontinuation of chronic morphine treatment). Therefore, the opioid-induced hyperalgesia can be viewed in the context of dependence/withdrawal rather than pain management, in line with clinical reports. There is convincing evidence of analgesic effects mediated by immune cell-derived opioid peptides in animal models and in humans. Together, MOP, DOP, and KOP receptors, and opioid peptides in immune cells can ameliorate pathological pain. The relevance of NOP receptors and N/OFQ in leukocytes, and of all opioid receptors, opioid peptides and N/OFQ in native glia for pain control is yet to be clarified.

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Section: Gliamentioning

confidence: 99%

Section: Gliamentioning

confidence: 99%

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

2020

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“…For example, the density of Iba-1positive microglia in cortex and striatum are reduced after subchronic opioid treatment but increased again after spontaneous withdrawal 11 . Neuroinflammation also has a complex role in pain and tolerance to opioid analgesics and microglia have been recently identified as playing a key role in the paradoxical development of opioid-induced hyperalgesia, 12,13 although there are likely multiple other mechanisms involved. Morphine potentiates lipopolysaccharide-induced microglia activation via both opioid receptor mediated and TLR4-mediated pathways 14 .…”

Section: Opioid Abuse Has Reached Epidemic Proportions In the Unitedmentioning

confidence: 99%

RiboTag-Seq Reveals a Compensatory cAMP Responsive Gene Network in Striatal Microglia Induced by Morphine Withdrawal

Coffey

Lesiak

Marx

et al. 2020

Preprint

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Microglia have recently been implicated in dependence to opioids. To investigate this directly, we used RNA sequencing of ribosome associated RNAs from striatal microglia (RiboTag-Seq) after the induction of morphine tolerance and then the precipitation of withdrawal by naloxone. We detected large, inverse changes in RNA translation following opioid tolerance and withdrawal, and bioinformatics analysis revealed an intriguing upregulation of cAMP-associated genes that are involved in microglial motility, morphology, and interactions with neurons. Three-dimensional histological reconstruction of microglia revealed changes in process branching and termination following opioid tolerance that were rapidly reversed during withdrawal and were consistent with cAMP effects on microglia morphology. Direct activation of Gicoupled DREADD receptors in microglia, rather than mimicking the effects of morphine, exacerbated opioid withdrawal. Together these indicate that microglial response to cAMP signaling can mitigate the rapid manifestations of opioid withdrawal. inverse relationship between gene expression changes duringFigure 4. Differential Expression Analysis | Naloxone administration to non-morphine-dependent animals has little effect on gene expression in the a, IP samples or d, Input samples. Morphine tolerance produces roughly equal numbers of upregulated and downregulated DEGs in both the b, IP sample and e, Input sample. Naloxone administration to morphine dependent animals produces mainly upregulation of DEGs in both the c, IP and f, Input samples. Gene expression changes during withdrawal are inversely correlated to gene expression changes during morphine tolerance in both the g, IP sample and h, Input sample.Roughly half of IP DEGs were also differentially expressed in the Input samples for both i, morphine tolerance and j, withdrawal, suggesting a common mechanism of action in neurons and microglia.

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“…Changes in the activity of BK Ca channels in microglia have been demonstrated to be associated with morphine‐induced hyperalgesia (Hayashi et al, ). As reported previously (Chen et al, ), the activity of BK Ca channels was detected in mHippoE‐14 neurons.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of I_Na, I_K(M), and I_K(erg) unlinked to interaction with opioid receptors

Liu

Hsiao

Wang

et al. 2019

Drug Development Research

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Nalbuphine (NAL) is recognized as a mixer with the κ‐opioid receptor agonist and the μ‐opioid receptor antagonist. However, whether this drug causes any modifications in neuronal ionic currents is unclear. The effects of NAL on ionic currents in mHippoE‐14 hippocampal neurons were investigated. In the whole‐cell current recordings, NAL suppressed the peak amplitude of voltage‐gated Na+ current (INa) with an IC50 value of 1.9 μM. It shifted the steady‐state inactivation curve of peak INa to the hyperpolarized potential, suggesting that there is the voltage dependence of NAL‐mediated inhibition of peak INa. In continued presence of NAL, subsequent application of either dynorphin A1‐13 (1 μM) or naloxone (30 μM) failed to modify its suppression of peak INa. Tefluthrin (Tef; 10 μM), a pyrethroid known to activate INa, increased peak INa with slowed current inactivation; however, further application of NAL suppressed Tef‐mediated suppression of peak INa followed by an additional slowing of current inactivation. In addition, NAL suppressed the amplitude of M‐type K+ current [IK(M)] with an IC50 value of 5.7 μM, while it slightly suppressed erg‐mediated and delayed‐rectifier K+ currents. In the inside‐out current recordings, NAL failed to modify the activity of large‐conductance Ca2+‐activated K+ channels. In differentiated NG108‐15 neuronal cells, NAL also suppressed the peak INa, and subsequent addition of Tef reversed NAL‐induced suppression of INa. Our study highlights the evidence that in addition to modulate opioid receptors, NAL has the propensity to interfere with ionic currents including INa and IK(M), thereby influencing the functional activities of central neurons.

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BK channels in microglia are required for morphine-induced hyperalgesia

Cited by 60 publications

References 68 publications

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

RiboTag-Seq Reveals a Compensatory cAMP Responsive Gene Network in Striatal Microglia Induced by Morphine Withdrawal

Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of I_Na, I_K(M), and I_K(erg) unlinked to interaction with opioid receptors

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BK channels in microglia are required for morphine-induced hyperalgesia

Cited by 60 publications

References 68 publications

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

Opioid Receptors in Immune and Glial Cells—Implications for Pain Control

RiboTag-Seq Reveals a Compensatory cAMP Responsive Gene Network in Striatal Microglia Induced by Morphine Withdrawal

Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of INa, IK(M), and IK(erg) unlinked to interaction with opioid receptors

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Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of I_Na, I_K(M), and I_K(erg) unlinked to interaction with opioid receptors