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Involvement of the nociceptin opioid peptide receptor in morphine-induced antinociception, tolerance and physical dependence in female mice

Abstract

Nociceptin opioid peptide (NOP) receptor modulates pain transmission and is considered a prospective target for pain management. Under acute pain conditions in rodents, however, no definitive conclusions about effects of systemically intervening NOP receptors on nociception, classical opioid-induced antinociception, tolerance and physical dependence have been drawn. Given that opioid analgesia has sex differences, and females experience greater pain and consume more opioids, clarifying these issues in females will help develop novel analgesics. To clarify the role of NOP receptors on the pharmacological profiles of µ-opioid receptor agonists, in this study, a selective agonist (SCH221510) and antagonist (SB612111) of the NOP receptor were subcutaneously administered in female mice in multiple animal models. In hot-plate test, neither SCH221510 (3 and 10 mg/kg, sc) nor SB612111 (10 mg/kg, sc) produced significant antinociception. SCH221510 (3 mg/kg, sc) attenuated but SB612111 (10 mg/kg, sc) enhanced morphine-induced antinociception, with rightward and leftward shift of morphine dose-response curves, respectively. SCH221510 (3 mg/kg, sc) combined with morphine (10 mg/kg, sc) accelerated the development of morphine antinociceptive tolerance. Conversely, SB612111 (10 mg/kg, sc) delayed morphine tolerance development. Neither SCH221510 (3 mg/kg, sc) nor SB612111 (10 mg/kg, sc) statistically significantly altered the development of morphine-induced physical dependence. Therefore, systemic activation of NOP receptors attenuated morphine antinociception to acute thermal stimuli, facilitated morphine-induced antinociceptive tolerance but did not robustly alter physical dependence in female mice. Systemic blockade of NOP receptors produced opposite actions. These findings demonstrate that N/OFQ-NOP receptor system plays diverse roles in modulating pharmacological profiles of µ-opioid receptor agonists.

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Data availability

Datasets from this study are available from the corresponding authors on reasonable request.

Code availability

SPSS 26.0 and GraphPad Prism 7.04.

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Funding

This work was supported by the National Natural Science Foundation of China (81874310).

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NW and JL designed the study. XQH, ZYW and JMC performed the experiments. NW, XQH, ZYW and JMC analyzed the data. NW, XQH and JL wrote the manuscript.

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Correspondence to Ning Wu or Jin Li.

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All animal procedures were approved by the Institutional Review Committee for the Use of Animals (Beijing Institute of Pharmacology and Toxicology, China; Ethical approval number: IACUC of AMMS-06-2019-002) and were performed in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals (NIH Publication No. 80 − 23). None of the authors performed any human experiments as part of this research.

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Hao, XQ., Wang, ZY., Chen, JM. et al. Involvement of the nociceptin opioid peptide receptor in morphine-induced antinociception, tolerance and physical dependence in female mice. Metab Brain Dis (2021). https://doi.org/10.1007/s11011-021-00783-8

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Keywords

  • Nociceptin opioid peptide receptor
  • Acute pain
  • Morphine
  • Antinociception
  • Tolerance
  • Physical dependence