Tolerance to repeated microinjection of morphine into the periaqueductal gray is associated with changes in the behavior of off- and on-cells in the rostral ventromedial medulla of rats

Although the administration of opioids is the most effective treatment for pain, their efficacy is limited by the development of tolerance. The midbra in periaqueductal gray matter (PAG) participates in opioid analgesia and to lerance. Microinjection of morphine into PAG produces antinociception, prob ably through neurons in the rostral ventromedial medulla (RVM), namely thro ugh the activation of off-cells, which inhibit nociception, and the inhibit ion of on-cells, which facilitate nociception. After its repeated microinje ction into the PAG morphine loses effectiveness. The present study sought t o determine whether tolerance to FAG morphine administration is associated with changes in the behavior of RVM neurons. Morphine (0.5 mug/0.4 mul) or saline (0.4 mul) was microinjected into the ventrolateral FAG twice daily. Initially morphine caused a latency increase in the hot plate test (antinoc iception) but this: effect disappeared by day 3 (tolerance). On day 4, each rat was: anesthetized with halothane and recordings were made from off- an d on-cells in the RVM, i.e. from neurons that decrease or increase their fi ring, respectively, just before a heat-elicited tail flick. In contrast to saline-pretreated rats, FAG microinjection of morphine in tolerant animals did not change the baseline activity of off- or on-cells, did not prevent t he off-cell pause or the on-cell activation upon tail heating, and did not lengthen the tail flick latency. However, microinjection of kainic acid int o the FAG (I) caused off-cells to become continuously active and on-cells t o become silent, and (2) prevented the tail flick, i.e. exactly what morphi ne did before tolerance developed. These results demonstrate a corresponden ce between neuronal and behavioral measures of tolerance to FAG opioid admi nistration, and suggest that tolerance is mediated by a change in opioid-se nsitive neurons within the FAG. (C) 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.