Trace amine-associated receptor 1 (TAAR1) plays a critical role in regulating dopamine transmission. Previous studies showed that pharmacologically or genetically manipulating the activity of TAAR1 modulates addiction-like behaviors associated with psychostimulants. However, little is known about whether TAAR1 modulation would regulate the behavioral effects of opioids.
Here, we systematically assessed the effects of the selective TAAR1 partial agonist RO5263397 on the addiction-related and antinociceptive effects of morphine in male rats and mice.
We found that RO5263397 attenuated the expression of morphine-induced behavioral sensitization in wildtype but not TAAR1 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 behavior in rats. RO5263397 alone did not trigger the reinstatement of morphine-seeking behavior or change locomotor activity in rats that had 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 behavior 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 TAAR1 activation selectively attenuated the reinforcing but not withdrawal or antinociceptive effects of morphine, suggesting that selective TAAR1 agonists might be useful to combat opioid addiction while sparing the strong analgesic effects.

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