Abstract
Although morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance. Microglia-to-neuron signalling is critically involved in pain hypersensitivity. However, molecules that control microglial cellular state under chronic morphine treatment remain unknown. Here we show that the microglia-specific subtype of Ca(2+)-activated K(+) (BK) channel is responsible for generation of MIH and anti-nociceptive tolerance. We find that, after chronic morphine administration, an increase in arachidonic acid levels through the μ-opioid receptors leads to the sole activation of microglial BK channels in the spinal cord. Silencing BK channel auxiliary β3 subunit significantly attenuates the generation of MIH and anti-nociceptive tolerance, and increases neurotransmission after chronic morphine administration. Therefore, microglia-specific BK channels contribute to the generation of MIH and anti-nociceptive tolerance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics, Opioid / adverse effects*
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Animals
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Arachidonic Acid / metabolism
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Cerebral Cortex / cytology
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Disease Models, Animal
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Drug Tolerance
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Gene Silencing
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Humans
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Hyperalgesia / chemically induced
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Hyperalgesia / pathology*
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / antagonists & inhibitors
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / genetics
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microglia / drug effects*
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Microglia / metabolism
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Morphine / adverse effects*
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Mutation
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Neurons
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Nociception / drug effects
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Nociception / physiology
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Pain / drug therapy
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Pain / metabolism*
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Pain Measurement
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Peptides / pharmacology
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Primary Cell Culture
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Rats
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Rats, Wistar
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Receptors, Opioid, mu / metabolism
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Receptors, Purinergic P2X4 / metabolism
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Spinal Cord / cytology
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Spinal Cord / pathology
Substances
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Analgesics, Opioid
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Kcnma1 protein, mouse
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
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Peptides
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Receptors, Opioid, mu
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Receptors, Purinergic P2X4
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Arachidonic Acid
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Morphine
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iberiotoxin