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

Abstract

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.

Fentanyl depression of respiration: Comparison with heroin and morphine

“…In the present study, we observed that when morphine pretreated mice were challenged with either fentanyl or morphine, the degree of cross tolerance to fentanyl was less than the tolerance to morphine itself. A similar reduced level of cross tolerance between fentanyl and morphine has been reported in studies of rodent locomotor activity (Brase, ) and antinociception (Bobeck, Schoo, Ingram, & Morgan, ; Paronis & Holzman, ), although one study has reported equal cross tolerance between morphine and fentanyl on antinociception (Romero, Miranda, & Puig, ). Cross tolerance develops between drugs acting at the same receptor, but the degree of cross tolerance will depend upon agonist intrinsic efficacy.…”

Differences in antinociceptive signalling mechanisms following morphine and fentanyl microinjections into the rat periaqueductal gray

“…Even though morphine and fentanyl are two of the most commonly used opioids to treat pain, morphine and fentanyl appear to engage different signalling pathways when microinjected into the periaqueductal gray (PAG). Antinociception produced by PAG morphine administration has a slower onset and longer duration than fentanyl (Bobeck, McNeal, & Morgan, ), is disrupted by blocking G‐protein signalling by administration of pertussis toxin whereas fentanyl antinociception is not (Bobeck, Ingram, Hermes, Aicher, & Morgan, ; Bodnar, Paul, Rosenblum, Liu, & Pasternak, ), and does not show cross‐tolerance to fentanyl following repeated PAG microinjections (Bobeck, Haseman, Hong, Ingram, & Morgan, ; Bobeck, Schoo, Ingram, & Morgan, ). These differences between morphine and fentanyl could be caused by selective activation of distinct signalling pathways or selective activation of pre‐ or postsynaptic MORs.…”

Unique Pharmacology, Brain Dysfunction, and Therapeutic Advancements for Fentanyl Misuse and Abuse

“…The reinforcing effects of fentanyl increase in morphine-withdrawn rats, reflected by a rightward shift of the fentanyl dose-response curve with an increase in maximal effectiveness, whereas the reinforcing effects of fentanyl decrease in opioid-dependent rats [ 33 ]. However, no antinociceptive cross-tolerance occurs with repeated microinjections of morphine and fentanyl into the ventrolateral periaqueductal gray, which may be attributable to the different signaling mechanisms that mediate morphine- and fentanyl-induced antinociception [ 34 , 35 ].…”