Lack of Antinociceptive Cross-Tolerance With Co-Administration of Morphine and Fentanyl Into the Periaqueductal Gray of Male Sprague-Dawley Rats

Tolerance to the antinociceptive effect of mu-opioid receptor agonists, such as morphine and fentanyl, greatly limits their effectiveness for long-term use to treat pain. Clinical studies have shown that combination therapy and opioid rotation can be used to enhance opioid-induced antinociception once tolerance has developed. The mechanism and brain regions involved in these processes are unknown. The purpose of this study was to evaluate the contribution of the ventrolateral periaqueductal gray (vlPAG) to antinociceptive tolerance and cross-tolerance between administration and co-administration of morphine and fentanyl. Tolerance was induced by pretreating rats with morphine or fentanyl or low-dose combination of morphine and fentanyl into the vlPAG followed by an assessment of the cross-tolerance to the other opioid. In addition, tolerance to the combined treatment was assessed. Cross-tolerance did not develop between repeated vlPAG microinjections of morphine and fentanyl. Likewise, there was no evidence of cross-tolerance from morphine or fentanyl to the co-administration of morphine and fentanyl. Co-administration did not cause cross-tolerance to fentanyl. Cross-tolerance was only evident to morphine or morphine and fentanyl combined in rats pretreated with co-administration of low doses of morphine and fentanyl. This finding is consistent with the functionally selective signaling that has been reported for antinociception and tolerance after morphine and fentanyl binding to the mu-opioid receptor. This research supports the notion that combination therapy and opioid rotation may be useful clinical practices to decrease opioid tolerance and other side effects. Perspective: This preclinical study shows that there is a decrease in cross-tolerance between morphine and fentanyl within the periaqueductal gray, which is a key brain region in opioid antinociception and tolerance.