title: Pain after discontinuation of morphine treatment is associated with synaptic increase of GluA4-containing AMPAR in the dorsal horn of the spinal cord.
abstract: Withdrawal from prescribed opioids results in increased pain sensitivity, which prolongs the treatment. This pain sensitivity is attributed to neuroplastic changes that converge at the spinal cord dorsal horn. We have recently reported that repeated morphine administration triggers an insertion of GluA2-lacking (Ca(2+)-permeable) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) in the hippocampus. This finding together with the reported involvement of AMPAR in the mechanisms underlying inflammatory pain led us to hypothesize a role for spinal AMPAR in opioid-induced pain behavior. Mice treated with escalating doses of morphine showed hypersensitivity to mechanical stimulation. Intrathecal administration of a Ca(2+)-permeable AMPAR selective blocker disrupted morphine-induced mechanical sensitivity. Analysis of the expression and phosphorylation levels of AMPAR subunits (GluA1/2/3/4) in homogenates and in postsynaptic density fractions from spinal cord dorsal horns showed an increase in GluA4 expression and phosphorylation in the postsynaptic density after morphine. Co-immunoprecipitation analyses suggested an increase in GluA4 homomers (Ca(2+)-permeable AMPAR) and immunohistochemical staining localized the increase in GluA4 levels in laminae III-V. The excitatory postsynaptic currents (EPSCs) recorded in laminae III-V showed enhanced sensitivity to Ca(2+)-permeable AMPAR blockers in morphine-treated mice. Furthermore, current-voltage relationships of AMPAR-mediated EPSCs showed that rectification index (an indicator of Ca(2+)-permeable AMPAR contribution) is increased in morphine-treated but not in saline-treated mice. These effects could be reversed by infusion of GluA4 antibody through patch pipette. This is the first direct evidence for a role of GluA4-containing AMPAR in morphine-induced pain and highlights spinal GluA4-containing AMPAR as targets to prevent the morphine-induced pain sensitivity.
authors: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors: David
authors: D
authors: Cabañero
authors: Alyssa
authors: A
authors: Baker
authors: Shengtai
authors: S
authors: Zhou
authors: Gregory L
authors: GL
authors: Hargett
authors: Takeshi
authors: T
authors: Irie
authors: Yan
authors: Y
authors: Xia
authors: Hélène
authors: H
authors: Beaudry
authors: Louis
authors: L
authors: Gendron
authors: Zara
authors: Z
authors: Melyan
authors: Susan M
authors: SM
authors: Carlton
authors: Jose A
authors: JA
authors: Morón
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage*; D010146:Pain / Q000378:metabolism* / Q000473:pathology; D010147:Pain Measurement / Q000379:methods; D020671:Posterior Horn Cells / Q000378:metabolism* / Q000473:pathology; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D018091:Receptors, AMPA; C104724:glutamate receptor ionotropic, AMPA 4; D009020:Morphine
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