(2R, 6R)-hydroxynorketamine (HNK) reverses mechanical hypersensitivity in a model of localized inflammatory pain. (15th December 2022) - Yost, Jonathan G.
Abstract: The ketamine metabolite (2 R, 6 R )-hydroxynorketamine, or (2 R, 6 R )-HNK, was recently reported to evoke antinociception in response to a noxious thermal stimulus in healthy mice and reverse mechanical hypersensitivity in a murine model of neuropathic pain. This study reports the behavioral effects of (2 R, 6 R )-HNK in male and female C57BL/6J mice exposed to a localized inflammatory pain condition and the broad pharmacological mechanism underlying this effect. Hind paw intraplantar injection of λ-carrageenan (CARR) caused inflammation and mechanical hypersensitivity in mice within 2 h, lasting at least 48 h. Administration of (2 R, 6 R )-HNK (10–30 mg/kg i.p.) 2 h following CARR injection significantly reversed mechanical hypersensitivity within 1 h in male and female mice, and the effect persisted for 24 h following a single dose. The magnitude and timing of the analgesic effect of (2 R, 6 R )-HNK were comparable to the non-steroidal anti-inflammatory drug carprofen. The reversal of hypersensitivity by (2 R, 6 R )-HNK was blocked at 4 and 24 h after administration by pretreatment with the AMPA receptor antagonist NBQX and was not accompanied by changes in locomotor activity. These findings reinforce the growing evidence supporting (2 R, 6 R )-HNK as a novel analgesic in multiple preclinical pain models and further support an AMPAR-dependent mechanism of action. Significance: The ketamine metabolite (2 R, 6 R )-HNK reversed mechanical hypersensitivity associated with localized inflammation with onset less than 1 h and duration greater than 24 h, an effect comparable to the NSAID carprofen. Reversal of mechanical hypersensitivity by (2 R, 6 R )-HNK is AMPAR-dependent. Highlights: The ketamine metabolite (2 R, 6 R )-HNK reversed mechanical hypersensitivity from localized hind paw inflammation. Reversal of inflammatory mechanical hypersensitivity by (2 R, 6 R )-HNK was comparable in magnitude to the NSAID carprofen. Reversal of hypersensitivity by (2 R, 6 R )-HNK was blocked by pretreatment with the AMPA receptor antagonist NBQX. (2 R, 6 R )-HNK is a novel analgesic in multiple preclinical pain models.