Analysis of morphine-induced changes in the activity of periaqueductal gray neurons in the intact rat

• Different subsets of PAG neurons are excited and inhibited by noxious stimuli.
• Morphine has mixed effects on the activity of PAG neurons in anesthetized rats.
• Morphine causes a small increase in the activity of most PAG neurons in awake rats.

Microinjection of morphine into the periaqueductal gray (PAG) produces antinociception. In vitro slice recordings indicate that all PAG neurons are sensitive to morphine either by direct inhibition or indirect disinhibition. We tested the hypothesis that all PAG neurons respond to opioids in vivo by examining the extracellular activity of PAG neurons recorded in lightly anesthetized and awake rats. Spontaneous activity was less than 1 Hz in most neurons. Noxious stimuli (heat, pinch) caused an increase in activity in 57% and 75% of the neurons recorded in anesthetized and awake rats, respectively. The same noxious stimuli caused a decrease in activity in only 17% and 6% of neurons recorded in anesthetized and awake rats. Systemic administration of morphine caused approximately equal numbers of neurons to increase, decrease, or show no change in activity in lightly anesthetized rats. In contrast, administration of morphine caused an increase in the activity of 22 of the 27 neurons recorded in awake rats. No change in activity was evident in the remaining five neurons. Changes in activity caused by morphine were surprisingly modest (a median increase from 0.7 to 1.3 Hz). The small inconsistent effects of morphine are in stark contrast to the large changes produced by morphine on the activity of rostral ventromedial medulla (RVM) neurons or the widespread inhibition and excitation of PAG neurons treated with opioids in in vitro slice experiments. The relatively modest effects of morphine in the present study suggest that morphine produces antinociception by causing small changes in the activity of many PAG neurons.