Effects of blockade of glutamate NMDA receptors or of NO synthase on the development or the expression of associative or non-associative sensitization to locomotor activation by morphine.

ABSTRACT

The sensitization to the pharmacological actions of morphine is probably a critical factor in the addictive properties of this drug. A discrimination between associative and non-associative type of sensitization might be relevant for possible differences in drug effects on sensitization phenomena. Furthermore, blockade of NMDA receptors might lead to an inhibition of NO-synthesis, and, accordingly, both of these effects might influence sensitization phenomena in a similar way. Male Wistar rats were sensitized to morphine by administrations of 3 mg/kg of morphine i.p. on day 1, 3, 5, and 7 and saline on days 2, 4, and 6. In part of the animals, the administration of morphine was performed in association with conditional stimuli, CS (test cage plus an auditory and an olfactory stimulus), in the other part not (pseudoconditioned, PCS). On day 17, the sensitization was more pronounced in the CS than the PCS group. The effects of dizocilpine (MK-801; 0.1 mg/kg i.p.), a blocker of NMDA glutamate receptors, or of L-NAME (N(G)-nitro-L-arginine methylester; 10 mg/kg i.p.), a non-specific inhibitor of NO synthase and the effect of N(omega)-propyl-L-arginine (20 mg/kg i.p.), a specific inhibitor of neuronal NO synthase, on expression or development of sensitization to morphine was studied. Neither MK-801 nor L-NAME influenced the development of associative and non-associative behavioural sensitization to morphine. The expression of sensitization to morphine was not influenced by MK-801. L-NAME inhibited the expression of associative, but not of non-associative sensitization. Surprisingly, inhibition of neuronal NO synthase, did not influence the expression of associative sensitization. We suggest that NMDA receptors were not involved in development or expression of both types of sensitization. Furthermore, the manifestation of the associative, but not the non-associative sensitization to morphine appeared to be dependent on a type of NO synthase, which is not the neuronal NO synthase, but probably the inducible NOS.