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The current study aims at investigating the antinociceptive effect of intranasal (<jats:italic>2R, 6R<\/jats:italic>)\u2010HNK using pre\u2010clinical models of acute pain. Additionally, the behavioural and neurophysiological safety analyses were carried out for the effective time window. Antinociceptive efficacy of (<jats:italic>2R, 6R<\/jats:italic>)\u2010HNK was evaluated using the hot plate test and Hargreaves' plantar test. The formalin test was carried out in both the acute and tonic phases. The neurophysiological and behavioural safety analyses were carried out separately for the haemodynamic function, cortical electroencephalography (EEG), and spontaneous behavioural functions. Analgesic effect of (<jats:italic>2R, 6R<\/jats:italic>)\u2010HNK was evident by a significant increase in paw\u2010withdrawal latency in both Hargreaves' and hot plate tests. Additionally, the (<jats:italic>2R, 6R<\/jats:italic>)\u2010HNK showed a significant ameliorative effect on pain\u2010related behaviour in the second phase of the formalin test. (<jats:italic>2R, 6R<\/jats:italic>)\u2010HNK exhibited an anxiolytic effect without causing any significant changes in locomotor activity and haemodynamic parameters. Power spectral density (PSD) analysis of electroencephalogram revealed no significant changes except a comparative increase in the gamma band range. Both the locomotor functions in the open field test and the PSD value of delta wave indicated no sedative effect at the given dose of (<jats:italic>2R, 6R<\/jats:italic>)\u2010HNK. The results demonstrated the pain\u2010alleviating effect of (<jats:italic>2R, 6R<\/jats:italic>)\u2010HNK without compromising the neurophysiological and behavioural function. Therefore, intranasal (<jats:italic>2R, 6R<\/jats:italic>)\u2010HNK is suggested as a safe candidate for further clinical study in the management of acute pain.<\/jats:p>","DOI":"10.1111\/1440-1681.13737","type":"journal-article","created":{"date-parts":[[2022,11,13]],"date-time":"2022-11-13T06:28:27Z","timestamp":1668320907000},"page":"169-177","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Intranasal (<i>2R, 6R<\/i>)\u2010hydroxynorketamine for acute pain: Behavioural and neurophysiological safety analysis in mice"],"prefix":"10.1111","volume":"50","author":[{"given":"Nidhi","family":"Goswami","sequence":"first","affiliation":[{"name":"Division of Behavioral Neuroscience Institute of Nuclear Medicine &amp; Allied Sciences  Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohd","family":"Aleem","sequence":"additional","affiliation":[{"name":"Division of Behavioral Neuroscience 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