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The behavioral effects of a mixed efficacy antinociceptive peptide, VRP26, following chronic administration in mice

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Abstract

Rationale

VRP26 displays mu opioid receptor agonist and delta opioid receptor antagonist activity in vitro, a pharmacological profile purported to produce reduced tolerance, dependence, and rewarding effects. We hypothesized that VRP26 would display reduced adverse effects after chronic administration as compared with the traditional opioid analgesic fentanyl.

Objective

The aim of this study is to explore the development of tolerance, dependence, and conditioned place preference of VRP26 as compared with the traditional opioid analgesic fentanyl.

Methods

The antinociceptive effects of VRP26 and fentanyl were assessed using the mouse warm water tail withdrawal (WWTW) assay. Measurement of antinociceptive tolerance and physical dependence occurred after 7 days of continuous administration of either fentanyl (0.3 mg/kg/day) or VRP26 (10 mg/kg/day); tolerance was measured by a shift in the antinociceptive dose response curve in the WWTW assay. Physical dependence was determined by observation of withdrawal symptoms after precipitated withdrawal. Rewarding effects were measured by the ability of VRP26 or fentanyl to produce conditioned place preference.

Results

Fentanyl produced significant tolerance and dependence, as well as significant conditioned place preference. VRP26 produced neither tolerance nor physical dependence, nor did it produce significant conditioned place preference.

Conclusions

These results suggest that chronic treatment with VRP26 may produce less tolerance or physical dependence than chronic treatment with clinically available mu opioid analgesics such as fentanyl. Additionally, VRP26 produces less rewarding effects than fentanyl. This desirable in vivo profile may be due to the mixed efficacy nature of VRP26 and could provide the framework for safer opioid analgesics.

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Acknowledgments

The authors thank Dr. Kenner Rice for his generous gift of SNC80 and John. R. Traynor for his generous gift of mu opioid receptor knockout mice.

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Authors and Affiliations

  1. Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, MI, 48109, USA

    Jessica P. Anand, Brett T. Boyer & Emily M. Jutkiewicz

  2. Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA

    Henry I. Mosberg

Authors
  1. Jessica P. Anand
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  2. Brett T. Boyer
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  3. Henry I. Mosberg
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  4. Emily M. Jutkiewicz
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Corresponding authors

Correspondence to Henry I. Mosberg or Emily M. Jutkiewicz.

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Funding and disclosure

The authors have no conflicts to disclose. This work was funded by NIH Grant DA003910 and R01 DA039997. J.P.A. was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award T32 DA007267. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Anand, J.P., Boyer, B.T., Mosberg, H.I. et al. The behavioral effects of a mixed efficacy antinociceptive peptide, VRP26, following chronic administration in mice. Psychopharmacology 233, 2479–2487 (2016). https://doi.org/10.1007/s00213-016-4296-8

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  • DOI: https://doi.org/10.1007/s00213-016-4296-8

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