Abstract
Mechanisms of acute pain transition to chronic pain are not fully understood. Here we demonstrate an active role of β-arrestin 2 (Arrb2) in regulating spinal cord NMDA receptor (NMDAR) function and the duration of pain. Intrathecal injection of the mu-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin produces paradoxical behavioural responses: early-phase analgesia and late-phase mechanical allodynia which requires NMDAR; both phases are prolonged in Arrb2 knockout (KO) mice. Spinal administration of NMDA induces GluN2B-dependent mechanical allodynia, which is prolonged in Arrb2-KO mice and conditional KO mice lacking Arrb2 in presynaptic terminals expressing Nav1.8. Loss of Arrb2 also results in prolongation of inflammatory pain and neuropathic pain and enhancement of GluN2B-mediated NMDA currents in spinal lamina IIo not lamina I neurons. Finally, spinal over-expression of Arrb2 reverses chronic neuropathic pain after nerve injury. Thus, spinal Arrb2 may serve as an intracellular gate for acute to chronic pain transition via desensitization of NMDAR.
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 / pharmacology
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Animals
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Chronic Pain / etiology
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Chronic Pain / pathology*
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Disease Models, Animal
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Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
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Humans
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Hyperalgesia / chemically induced
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Hyperalgesia / pathology
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Injections, Spinal
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Male
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Mice
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Mice, Inbred ICR
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Mice, Knockout
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N-Methylaspartate / pharmacology
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Neuralgia / etiology
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Neuralgia / pathology*
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Neurons / drug effects
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Neurons / metabolism*
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Peripheral Nerve Injuries / etiology
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Peripheral Nerve Injuries / pathology*
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Receptors, Opioid, mu / antagonists & inhibitors
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Spinal Cord Dorsal Horn / cytology
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Spinal Cord Dorsal Horn / metabolism
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Substantia Gelatinosa / cytology
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Substantia Gelatinosa / metabolism*
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Time Factors
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beta-Arrestin 2 / genetics
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beta-Arrestin 2 / metabolism*
Substances
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Analgesics, Opioid
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Arrb2 protein, mouse
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NR2B NMDA receptor
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Receptors, N-Methyl-D-Aspartate
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Receptors, Opioid, mu
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beta-Arrestin 2
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Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
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N-Methylaspartate