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Background and Purpose  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.    Experimental Approach  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  GABA A   receptor‐mediated inhibitory postsynaptic currents ( IPSCs ) in  VLPAG  neurons were evaluated in slices from the  FBC  model.    Key Results  The supraspinal antinociceptive effects of oxycodone, but not morphine, were abolished by blocking  G  protein‐gated inwardly rectifying potassium1 ( K ir  3.1) channels. In slices from the  FBC  model,  GABA ergic 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  K ir  3.1 channels.    Conclusion and Implications  Our results demonstrate that  K ir  3.1 channels are important for supraspinal antinociception and presynaptic  GABA  release inhibition by oxycodone in the  FBC  model. Enhanced  GABA ergic synaptic transmission at  VLPAG  neurons in the  FBC  model is an important site of supraspinal antinociception by oxycodone via  K ir  3.1 channel activation.

Enhanced GABA ergic synaptic transmission at VLPAG neurons and potent modulation by oxycodone in a bone cancer pain model