The role of the ventrolateral periaqueductal gray in the development of tolerance to morphine

Repeated administration of morphine into the periaqueductal gray (PAG) results in tolerance, implicating the PAG as an important site for the development of tolerance to systemically administered opiates. However, tolerance has also been produced from opiate administration into other sites, such as the spinal cord and the peripheral nervous system. These data raise questions about the relative contributions of each site in the development of tolerance to systemically administered opiates. Further, the degree to which other factors, such as drug administration cues and repeated nociceptive testing, contribute to tolerance from morphine administration into the ventrolateral periaqueductal gray (vPAG) is not known. The purpose of the following studies was to determine the relative importance of the vPAG in mediating morphine tolerance. Five studies were conducted. Experiment 1 blocked the effects of systemic morphine administration in the vPAG with the opiate antagonist, naloxone, which resulted in a significant attenuation of tolerance demonstrating the importance of the vPAG in mediating tolerance from systemic morphine administration. Experiment 2 prevented the activation of the descending pain system by the vPAG with microinjections of the GABAA agonist muscimol into the rostral ventromedial medulla (RVM) just prior to repeated morphine microinjections into the vPAG. Inactivation of the RVM did not prevent the development of tolerance to morphine microinjections into the vPAG indicating that antinociceptive feedback from vPAG activation is not necessary for the development of tolerance. Experiment 3 continuously administered morphine into the vPAG via an osmotic pump which showed that tolerance can develop without drug administration cues. However, Experiment 4 paired specific environmental cues with morphine administration into the vPAG and showed that drug administration cues can augment pharmacological tolerance albeit a small increase in tolerance. Experiment 5 paired repeated nociceptive testing with repeated morphine administration into the vPAG and showed that behavioral tolerance significantly augments pharmacological tolerance. The results demonstrate that the vPAG is a critical structure mediating tolerance from systemic morphine administration and factors such as drug administration cues and repeated nociceptive testing contribute to tolerance produced from the vPAG.