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Enhanced GABA ergic synaptic transmission at VLPAG neurons and potent modulation by oxycodone in a bone cancer pain model
Author(s) -
Takasu Keiko,
Ogawa Koichi,
Nakamura Atsushi,
Kanbara Tomoe,
Ono Hiroko,
Tomii Takako,
Morioka Yasuhide,
Hasegawa Minoru,
Shibasaki Masahiro,
Mori Tomohisa,
Suzuki Tsutomu,
Sakaguchi Gaku
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13039
Subject(s) - neurotransmission , oxycodone , neuroscience , chemistry , transmission (telecommunications) , excitatory postsynaptic potential , biochemistry , inhibitory postsynaptic potential , biology , computer science , receptor , opioid , telecommunications
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.