Tolerance to the antinociceptive effect of mu-opioid receptor (MOPr) 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 coadministration 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 assessment of 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 co-administration of morphine and fentanyl. Co-administration did not cause cross-tolerance to fentanyl. Crosstolerance was only evident to morphine or morphine and fentanyl combined in rats pretreated with co-administration of low-doses of morphine and fentanyl. In conclusion, cross-tolerance does not develop between morphine and fentanyl within the vlPAG. This finding is consistent with the functionally selective signaling that has been reported for antinociception and tolerance following morphine and fentanyl binding to the MOPr. This research supports the notion that combination therapy and opioid rotation may be useful clinical practices to reduce opioid tolerance and other side effects. Perspective: This preclinical study shows that there is a reduction in cross tolerance between morphine and fentanyl within the periaqueductal gray which is key brain region in opioid antinociception and tolerance.

Dopamine neurons in the ventrolateral periaqueductal gray (PAG) have been reported to contribute to antinociception. The objective of this study was to determine how this dopamine-mediated antinociception differs from what is known about morphine-induced antinociception. Microinjection of the dopamine receptor agonist apomorphine into the PAG produced a dose-dependent increase in hot plate latency and a decrease in open field activity that was greater in male than in female rats. The peak antinociceptive effect occurred 5 min after apomorphine administration. Surprisingly, the antinociceptive potency of apomorphine was enhanced following systemic administration of the opioid receptor antagonist naloxone in male, but not in female rats. The antinociceptive potency of microinjecting apomorphine into the ventrolateral PAG in male and female rats was also enhanced following twice-daily injections for 2 days. The characteristics of apomorphine-induced antinociception differ from previous reports of morphine antinociception following PAG microinjections in that morphine antinociception peaks at 15 min, is blocked by naloxone, and is susceptible to tolerance with repeated administration. These results indicate that apomorphine-induced antinociception is distinct from opioid-induced antinociception, and that dopamine receptor agonists may provide a novel approach to pain modulation.