Intranasal (2R, 6R)-hydroxynorketamine for acute pain: Behavioural and neurophysiological safety analysis in mice

Area of Science:

• Neuroscience
• Pharmacology
• Pain Management

Background:

• Ketamine possesses antinociceptive properties and is used for treatment-resistant depression.
• The efficacy and safety of (2R, 6R)-hydroxynorketamine (HNK), a ketamine metabolite, for acute pain are not well-established.

Purpose of the Study:

• To investigate the antinociceptive effects of intranasal (2R, 6R)-HNK in preclinical models of acute pain.
• To assess the behavioral and neurophysiological safety of (2R, 6R)-HNK within its effective time window.

Main Methods:

• Antinociceptive efficacy was evaluated using the hot plate test, Hargreaves' plantar test, and formalin test.
• Safety assessments included hemodynamic function, electroencephalography (EEG) power spectral density (PSD) analysis, and spontaneous behavioral functions (locomotor activity).

Main Results:

• Intranasal (2R, 6R)-HNK significantly increased paw-withdrawal latency in thermal pain tests.
• (2R, 6R)-HNK demonstrated significant pain reduction in the tonic phase of the formalin test and exhibited anxiolytic effects.
• No significant adverse effects were observed in locomotor activity, hemodynamic parameters, or EEG (except for a gamma band increase).

Conclusions:

• Intranasal (2R, 6R)-HNK exhibits significant pain-alleviating effects in preclinical models.
• The compound appears safe, with no compromise to neurophysiological or behavioral functions at the tested dose.
• (2R, 6R)-HNK is a promising candidate for further clinical investigation in acute pain management.