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Lack of effect of different pain-related manipulations on opioid self-administration, reinstatement of opioid seeking, and opioid choice in rats

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Abstract

Rationale and objective

Pain-related factors increase the risk for opioid addiction, and pain may function as a negative reinforcer to increase opioid taking and seeking. However, experimental pain-related manipulations generally do not increase opioid self-administration in rodents. This discrepancy may reflect insufficient learning of pain-relief contingencies or confounding effects of pain-related behavioral impairments. Here, we determined if pairing noxious stimuli with opioid self-administration would promote pain-related reinstatement of opioid seeking or increase opioid choice over food.

Methods

In Experiment 1, rats self-administered fentanyl in the presence or absence of repeated intraplantar capsaicin injections in distinct contexts to model context-specific exposure to cutaneous nociception. After capsaicin-free extinction in both contexts, we tested if capsaicin would reinstate fentanyl seeking. In Experiment 2, rats self-administered heroin after intraperitoneal (i.p.) lactic acid injections to model acute visceral inflammatory pain. After lactic acid-free extinction, we tested if lactic acid would reinstate heroin seeking. In Experiment 3, we tested if repeated i.p. lactic acid or intraplantar Complete Freund’s Adjuvant (CFA; to model sustained inflammatory pain) would increase fentanyl choice over food.

Results

In Experiments 1-2, neither capsaicin nor lactic acid reinstated opioid seeking after extinction, and lactic acid did not increase heroin-induced reinstatement. In Experiment 3, lactic acid and CFA decreased reinforcement rate without affecting fentanyl choice.

Conclusions

Results extend the range of conditions across which pain-related manipulations fail to increase opioid seeking in rats and suggest that enhanced opioid-addiction risk in humans with chronic pain involves factors other than enhanced opioid reinforcement and relapse.

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Acknowledgements

We thank Hannah Korah for technical assistance with i.v. surgeries.

Funding

The research was supported by 1FI2GM128603 (DJR), F32DA047026 (EAT), Intramural Research Program of NIDA (YS), and P30DA0333034 (SSN and MLB).

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Authors and Affiliations

  1. Behavioral Neuroscience Branch, IRP/NIDA/NIH, Baltimore, MD, USA

    David J. Reiner, Javier Orihuel, Sarah V. Applebey, Sarah M. Claypool & Yavin Shaham

  2. NIGMS, Bethesda, MD, USA

    David J. Reiner

  3. Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    E. Andrew Townsend, Matthew L. Banks & S. Stevens Negus

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  1. David J. Reiner
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  2. E. Andrew Townsend
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  3. Javier Orihuel
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  6. Matthew L. Banks
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Contributions

DJR, EAT, MLB, YS, and SSN conceptualized the research. DJR, EAT, JOM, SVA, and SMC performed the research and analyzed the data. DJR, EAT, JOM, YS, and SSN wrote the manuscript. All authors approved of the final version.

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Reiner, D.J., Townsend, E.A., Orihuel, J. et al. Lack of effect of different pain-related manipulations on opioid self-administration, reinstatement of opioid seeking, and opioid choice in rats. Psychopharmacology 238, 1885–1897 (2021). https://doi.org/10.1007/s00213-021-05816-9

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