Department of Psychology, University of Wisconsin Green Bay, Green Bay, Wisconsin, United States of America.
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
PLoS One. 2024 Apr 19;19(4):e0301848. doi: 10.1371/journal.pone.0301848. eCollection 2024.
Ketamine has been shown to produce analgesia in various acute and chronic pain states; however, abuse liability concerns have limited its utility. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to produce antidepressant-like effects similar to ketamine without abuse liability concerns. (2R,6R)-HNK produces sustained analgesia in models of chronic pain, but has yet to be evaluated in models of acute pain. The present study evaluated the efficacy of acute (2R,6R)-HNK administration (one injection) in assays of pain-stimulated (52- and 56-degree hot plate test and acetic acid writhing) and pain-depressed behavior (locomotor activity and rearing) in male and female C57BL/6 mice. In assays of pain-stimulated behaviors, (2R,6R)-HNK (1-32 mg/kg) failed to produce antinociception in the 52- and 56-degree hot plate and acetic acid writhing assays. In assays of pain-depressed behaviors, 0.56% acetic acid produced a robust depression of locomotor activity and rearing that was not blocked by pretreatment of (2R,6R)-HNK (3.2-32 mg/kg). The positive controls morphine (hot plate test) and ketoprofen (acetic acid writhing, locomotor activity, and rearing) blocked pain-stimulated and pain-depressed behaviors. Finally, the effects of intermittent (2R,6R)-HNK administration were evaluated in 52-degree hot plate and pain-depressed locomotor activity and rearing. Intermittent administration of (2R,6R)-HNK also did not produce antinociceptive effects in the hot plate or pain-depressed locomotor activity assays. These results suggest that (2R,6R)-HNK is unlikely to have efficacy in treating acute pain; however, the efficacy of (2R,6R)-HNK in chronic pain states should continue to be evaluated.
氯胺酮已被证明在各种急性和慢性疼痛状态下具有镇痛作用；然而，滥用倾向的问题限制了其应用。氯胺酮的代谢物（2R,6R）-羟基去甲氯胺酮（HNK）已被证明具有类似氯胺酮的抗抑郁作用，而没有滥用倾向的问题。（2R,6R）-HNK 在慢性疼痛模型中产生持续的镇痛作用，但尚未在急性疼痛模型中进行评估。本研究评估了急性（2R,6R）-HNK 给药（单次注射）在疼痛刺激（52 和 56 度热板试验和醋酸扭体试验）和疼痛抑制行为（运动活性和站立）测定中的疗效在雄性和雌性 C57BL/6 小鼠中。在疼痛刺激行为测定中，（2R,6R）-HNK（1-32mg/kg）在 52 和 56 度热板和醋酸扭体试验中均未产生镇痛作用。在疼痛抑制行为测定中，0.56%醋酸产生了强烈的运动活性和站立抑制，而（2R,6R）-HNK（3.2-32mg/kg）预处理并不能阻断这种抑制。阳性对照吗啡（热板试验）和酮洛芬（醋酸扭体试验、运动活性和站立）阻断了疼痛刺激和疼痛抑制行为。最后，评估了间歇性（2R,6R）-HNK 给药在 52 度热板和疼痛抑制运动活性和站立中的作用。间歇性给予（2R,6R）-HNK 也没有在热板或疼痛抑制运动活性试验中产生镇痛作用。这些结果表明，（2R,6R）-HNK 不太可能对治疗急性疼痛有效；然而，（2R,6R）-HNK 在慢性疼痛状态下的疗效应继续进行评估。
