title: Enhanced GABAergic synaptic transmission at VLPAG neurons and potent modulation by oxycodone in a bone cancer pain model.
abstract: OBJECTIVE
  We demonstrated previously that oxycodone has potent antinociceptive effects at supraspinal sites. In this study, we investigated changes in neuronal function and antinociceptive mechanisms of oxycodone at ventrolateral periaqueductal gray (VLPAG) neurons, which are a major site of opioid action, in a femur bone cancer (FBC) model with bone cancer-related pain.
  
  
  METHODS
  We characterized the supraspinal antinociceptive profiles of oxycodone and morphine on mechanical hypersensitivity in the FBC model. Based on the disinhibition mechanism underlying supraspinal opioid antinociception, the effects of oxycodone and morphine on GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in VLPAG neurons were evaluated in slices from the FBC model.
  
  
  RESULTS
  The supraspinal antinociceptive effects of oxycodone, but not morphine, were abolished by blocking G protein-gated inwardly rectifying potassium1 (Kir 3.1) channels. In slices from the FBC model, GABAergic synaptic transmission at VLPAG neurons was enhanced, as indicated by a leftward shift of the input-output relationship curve of evoked IPSCs, the increased paired-pulse facilitation and the enhancement of miniature IPSC frequency. Following treatment with oxycodone and morphine, IPSCs were reduced in the FBC model, and the inhibition of presynaptic GABA release by oxycodone, but not morphine was enhanced and dependent on Kir 3.1 channels.
  
  
  CONCLUSIONS
  Our results demonstrate that Kir 3.1 channels are important for supraspinal antinociception and presynaptic GABA release inhibition by oxycodone in the FBC model. Enhanced GABAergic synaptic transmission at VLPAG neurons in the FBC model is an important site of supraspinal antinociception by oxycodone via Kir 3.1 channel activation.
authors.affiliation: Pain and Neurology, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Takasu
authors.forename: Koichi
authors.initials: K
authors.lastname: Ogawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.forename: Tomoe
authors.initials: T
authors.lastname: Kanbara
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ono
authors.forename: Takako
authors.initials: T
authors.lastname: Tomii
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Morioka
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Mori
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D045744:Cell Line, Tumor; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D006930:Hyperalgesia / Q000188:drug therapy; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D008809:Mice, Inbred C3H; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010098:Oxycodone / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D010098:Oxycodone