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The imidazoline I2 receptor agonist 2-BFI reduces abuse-related effects of morphine: self-administration and drug discrimination

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Abstract

Rationale

Increasing evidence shows that imidazoline I2 receptor agonists enhance opioid-induced analgesia, suggesting that the combination of I2 receptor agonists with opioids could be a favorable strategy for pain control. However, the effect of I2 receptor agonists on the abuse liability of opioids is unknown. This study examined the impact of the I2 receptor agonist 2-BFI on some abuse-related behavioral effects of the opioid morphine in rats.

Objectives

The von Frey filament test was used to determine the antinociceptive effects of 2-BFI (intravenous, i.v.) in a rat model of complete Freund’s adjuvant (CFA)-induced inflammatory pain. IV self-administration was used to assess the reinforcing effects of 2-BFI alone and to assess the effects of non-contingent injections of 2-BFI (i.p.) on morphine self-administration. A two-lever drug discrimination paradigm in which rats were trained to discriminate 3.2 mg/kg morphine (i.p.) from saline was used to examine whether 2-BFI or another I2 receptor agonist 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride (BU224) affected the discriminative stimulus effects of morphine.

Results

2-BFI could not maintain reliable self-administration behavior in rats with no pain or CFA-treated inflammatory pain. However, pretreatment with 2-BFI (i.p.) produced dose-dependent decreases in the dose-effect curve of morphine self-administration. Both 2-BFI and BU224 did not substitute for morphine but significantly attenuated the discriminative stimulus effects of morphine.

Conclusions

These results suggest that I2 receptor agonists do not enhance, but in fact appear to decrease, the abuse liability of opioids, further supporting the potential utility of I2 receptor agonist-opioid combination therapy for pain control.

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Abbreviations

2-BFI:

2-(2-Benzofuranyl)-2-imidazoline

ANOVA:

Analysis of variance

BU224:

2-(4,5-Dihydroimidazol-2-yl)quinoline hydrochloride

CFA:

Complete Freund’s adjuvant

FR:

Fixed ratio

PWT:

Paw withdrawal threshold

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Funding

This work was supported by the National Institute on Drug Abuse of the National Institutes of Health (Award no. R01DA034806). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA

    Justin N. Siemian, Kristen Woodhouse & Jun-Xu Li

  2. Episcopal High School, Alexandria, VA, USA

    David H. Liu

  3. Research Triangle Institute, Research Triangle Park, NC, USA

    Yanan Zhang

Authors
  1. Justin N. Siemian
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  2. Kristen Woodhouse
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  3. David H. Liu
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  4. Yanan Zhang
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  5. Jun-Xu Li
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Contributions

The main idea of this study was from JS and J-XL. JS and J-XL designed the study, conducted the data analysis, and wrote the first draft of the manuscript. KW performed the pain tests. JS and DHL performed the self-administration experiments. KW performed the drug discrimination experiments. YZ provided 2-BFI and BU224. All authors contributed to and approved the final version of the manuscript.

Corresponding author

Correspondence to Jun-Xu Li.

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Siemian, J.N., Woodhouse, K., Liu, D.H. et al. The imidazoline I2 receptor agonist 2-BFI reduces abuse-related effects of morphine: self-administration and drug discrimination. Psychopharmacology 241, 479–487 (2024). https://doi.org/10.1007/s00213-023-06524-2

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  • DOI: https://doi.org/10.1007/s00213-023-06524-2

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