Differential susceptibility of the PAG and RVM to tolerance to the antinociceptive effect of morphine in the rat

The periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are part of a nociceptive modulatory system. Microinjection of morphine into either structure produces antinociception. Tolerance develops to ventrolateral PAG mediated antinociception with repeated microinjection of morphine. In contrast, there are no published reports of tolerance to morphine administration into the RVM. Three experiments were conducted to determine whether tolerance develops to morphine microinjections into the RVM. Experiment 1 compared tolerance to the antinociceptive effect of microinjecting morphine (5 μg/0.5 μl) into the PAG and RVM following daily injections for four consecutive days. Experiment 2 assessed tolerance to a range of morphine doses (2.5-20 μg) after injecting morphine into the RVM twice a day for two consecutive days. Experiment 3 followed a similar procedure except twice as many RVM injections were made (8 microinjections in 4 days). The degree to which tolerance developed to the antinociceptive effect of morphine was much greater with microinjections into the PAG compared to the RVM. There was a 64% drop in hot plate latency from the first to the fifth injection of morphine into the PAG, but only a 36% drop in latency following RVM microinjections. Reducing the interdose interval to two injections a day or increasing the total number of injections from 4 to 8 did not enhance the development of tolerance to RVM morphine administration. These data demonstrate that opioid-sensitive neurons in the RVM are relatively resistant to the development of tolerance compared to PAG neurons.