Sensitization to repeated morphine injection in the rat: possible involvement of A10 dopamine neurons

Daily administration of morphine in rats produces an increase in the motor stimulant effect of subsequent morphine injections. This study was designed to characterize the behavioral sensitization produced by daily morphine and to evaluate the involvement of the mesolimbic and/or mesocortical dopamine (DA) neurons. Daily injection of morphine for 7 days produced an increase in both horizontal and vertical photocell counts. There was no difference in morphine levels in the blood or brain between daily morphine- and daily saline-treated rats at 30 or 90 min after acute injection of morphine. The increase was present for 60 days after initiating treatment and was associated with increases in locomotion, rearing, sniffing, grooming and bursting. Sensitization to morphine was prevented by pretreatment with naloxone i.p. or naltrexone methobromide injection into the ventral tegmental area (VTA; location of A10 DA perikarya projecting to limbic and cortical areas). In contrast, pretreatment with the same dose of naltrexone methobromide injected into the nucleus accumbens (limbic DA terminal field) or lateral ventricles did not significantly attenuate behavioral sensitization to morphine. Daily intra-VTA injections of the mu opioid agonist Tyr-D-Ala-Gly-NMe-Phe-Gly-ol enhanced the behavioral stimulant effect of acute morphine. The effects of daily morphine treatment on DA systems were evaluated by measuring DA metabolism, dopa accumulation and DA depletion in the VTA and various DA terminal fields including the prefrontal cortex, nucleus accumbens and striatum.(ABSTRACT TRUNCATED AT 250 WORDS)