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Fentanyl-induced hyperalgesia and analgesic tolerance in male rats: common underlying mechanisms and prevention by a polyamine deficient diet

Abstract

Opioids are a mainstay of pain management but can induce unwanted effects, including analgesic tolerance and paradoxical hyperalgesia, either of which leads to increased pain. Clinically, however, the relationship between these two phenomena remains elusive. By evaluating changes in mechanical nociceptive threshold in male rats, we found that in contrast to a purely analgesic control response to a single subcutaneous administration of fentanyl (25 μg/kg), in rats subjected to inflammatory pain 2 weeks previously (Day0), the same test dose (D13) induced a bi-phasic response: initial decreased analgesia (tolerance) followed by hyperalgesia lasting several hours. Both the tolerance and hyperalgesia were further enhanced in rats that had additionally received fentanyl on D0. The dose-response profiles (5 fg to 50 μg/kg) of pain- and opioid-experienced rats were very different from pain/drug-naive rats. At ultra-low fentanyl doses (<5 ng/kg and <500 ng/kg for naïve control and pain/drug-experienced rats, respectively), solely hyperalgesia was observed in all cases. At higher doses, which now produced analgesia alone in naive rats, reduced analgesia (tolerance) coupled with hyperalgesia occurred in pain/fentanyl-experienced rats, with both phases increasing with dose. Transcriptomic and pharmacological data revealed that an overactivation of the spinal N-methyl-D-aspartate receptor-inducible NO synthase cascade plays a critical role in both acute tolerance and hyperalgesia, and together with the finding that the magnitudes of analgesia and associated hyperalgesia are negatively correlated, is indicative of closely related phenomena. Finally, a polyamine deficient diet prevented inducible NO synthase transcript upregulation, restored fentanyl’s analgesic efficacy and suppressed the emergence of hyperalgesia.

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Fig. 1: The effects of a single subcutaneous (sc) injection of fentanyl (25 µg/kg) on basal nociceptive threshold is dependent on previous pain and/or opioid experience.
Fig. 2: Negative relationship between bi-phasic analgesic and hyperalgesic effects of fentanyl.
Fig. 3: Acute effects of variable test fentanyl dosages (5 fg to 50 µg/kg) on nociceptive threshold are dependent on prior pain and opioid exposure.
Fig. 4: Involvement of a persistent NMDAR-iNOS cascade overactivation in the acute bi-phasic response to fentanyl in pain and opioid-experienced rats.
Fig. 5: Maintenance of acute analgesic efficacy and suppression of hyperalgesia by a polyamine deficient diet.

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Acknowledgements

We thank Jacques-Philippe Moulinoux, Ph.D., Professor (Faculté de Médecine and CHU de Rennes, Université de Rennes 1, 35043 Rennes, France) for gifting the Polyamine deficient rodent nutrient used in some experiments of this study. We are also grateful to Dr Romuald Nargeot for his invaluable assistance with our statistical analyses.

Funding

This work was supported by institutional and departmental resources from the Université de Bordeaux and Université de René Descartes Paris 5. We also received support from the ‘Conseil Régional d’Aquitaine Bordeaux’, the ‘Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation’, and the ‘Centre Nationale de la Recherche Scientifique’. The Universities of Bordeaux and Rennes 1 have a patent (co-inventors J.P. Moulinoux and G. Simonnet) for a human form of polyamine deficient diet adapted from standard rodent nutrient ingredients.

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GS and EL designed experiments. EL conducted behavioral studies with the help of MBB. Tissue sample preparation, mRNA level determinations and data analyses were performed by AM and MP. GS, EL and JS interpreted the data and wrote the paper. All authors discussed the results and commented on the paper.

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Correspondence to Guy Simonnet.

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Laboureyras, E., Boujema, M.B., Mauborgne, A. et al. Fentanyl-induced hyperalgesia and analgesic tolerance in male rats: common underlying mechanisms and prevention by a polyamine deficient diet. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01200-5

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