Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA.
School of Pharmacy, Yantai University, Yantai, China.
Br J Pharmacol. 2021 Feb;178(4):933-945. doi: 10.1111/bph.15335. Epub 2021 Jan 4.
Trace amine-associated TA receptors play critical roles in regulating dopamine transmission. Previous studies showed that pharmacologically or genetically manipulating the activity of TA receptors modulates addiction-like behaviours associated with psychostimulants. However, little is known about whether TA receptor modulation would regulate the behavioural effects of opioids.
Effects of the selective TA receptor partial agonist RO5263397 on the addiction-related and antinociceptive effects of morphine were systematically assessed in male rats and mice.
RO5263397 attenuated the expression of morphine-induced behavioural sensitization in wildtype but not TA receptor knockout mice. RO5263397 shifted the dose-effect curve of morphine self-administration downward and reduced the breakpoint in a progressive ratio schedule of reinforcement but did not affect food self-administration in rats. RO5263397 decreased the cue- and drug-induced reinstatement of morphine-seeking behaviour in rats. RO5263397 alone did not trigger reinstatement of morphine-seeking behaviour or change locomotor activity in rats with a history of morphine self-administration. However, RO5263397 did not affect the expression of morphine-induced conditioned place preference in mice or rats. RO5263397 did not affect naltrexone-precipitated jumping behaviour or naltrexone-induced conditioned place aversion in morphine-dependent mice. Furthermore, RO5263397 did not affect the analgesic effects of morphine in an acute nociception model in mice and a chronic pain model in rats.
These results indicated that TA receptor activation selectively attenuated the reinforcing, but not withdrawal or antinociceptive effects of morphine, suggesting that selective TA receptor agonists might be useful to combat opioid addiction, while sparing the analgesic effects.
痕量胺相关 TA 受体在调节多巴胺传递中发挥关键作用。先前的研究表明，药理学或遗传学上操纵 TA 受体的活性可以调节与精神兴奋剂相关的成瘾样行为。然而，对于 TA 受体调节是否会调节阿片类药物的行为效应知之甚少。
系统评估选择性 TA 受体部分激动剂 RO5263397 对吗啡的成瘾相关和镇痛作用在雄性大鼠和小鼠中的影响。
RO5263397 减弱了吗啡诱导的行为敏化在野生型但不是 TA 受体敲除小鼠中的表达。RO5263397 使吗啡自我给药的剂量-效应曲线向下转移，并降低了递增比率强化程序的断点，但不影响大鼠的食物自我给药。RO5263397 减少了吗啡寻求行为的线索和药物诱发的复燃。RO5263397 本身不会引发有吗啡自我给药史的大鼠的吗啡寻求行为复燃或改变其运动活动。然而，RO5263397 不影响吗啡诱导的条件位置偏好在小鼠或大鼠中的表达。RO5263397 不影响纳曲酮引发的跳跃行为或吗啡依赖小鼠的纳曲酮诱导的条件位置厌恶。此外，RO5263397 不影响吗啡在小鼠急性痛觉模型和大鼠慢性痛觉模型中的镇痛作用。
这些结果表明，TA 受体激活选择性地减弱了吗啡的强化作用，但不影响戒断或镇痛作用，表明选择性 TA 受体激动剂可能有助于对抗阿片类药物成瘾，同时保留镇痛作用。
