The absence of a functional peroxisome proliferator-activated receptor-alpha gene in mice enhances motor sensitizing effects of morphine, but not cocaine.

Neuroinflammation of the CNS seems to participate in sensitizing effects of drugs of abuse such as psychostimulants and morphine. The nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-alpha) plays a prominent role in several physiological processes including the inflammatory response, and its activation mediates a reduced production of pro-inflammatory factors. The objectives were to examine the involvement of nuclear PPAR-alpha in motor sensitization to morphine and cocaine, by using null mice (PPAR-alpha -/-mice), or the injection of a selective PPAR-alpha agonist, [[4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl] thio]acetic acid (WY14643), in morphine-treated mice. The findings indicate that PPAR-alpha plays an inhibitory role in the expression (not induction) of motor sensitization to morphine, but it is devoid of effects on sensitization to cocaine, suggesting that this nuclear receptor participates in motor activating effects of opiates but not psychostimulants. Furthermore, brain PPAR-alpha expression is upregulated after the highest dose of repeated morphine, but not chronic cocaine, suggesting that this receptor could play a homeostatic role. In accordance, systemic WY14643 was able to block sensitization to morphine, confirming that PPAR-alpha plays a homeostatic role opposing morphine-induced motor sensitization, likely through a reduction of inflammation-associated changes.