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Behavioral pharmacology of the mixed-action delta-selective opioid receptor agonist BBI-11008: studies on acute, inflammatory and neuropathic pain, respiration, and drug self-administration

  • Glenn W. StevensonEmail author
  • Denise Giuvelis
  • James Cormier
  • Katherine Cone
  • Phillip Atherton
  • Rebecca Krivitsky
  • Emily Warner
  • Brooke St. Laurent
  • Julio Dutra
  • Jean M. Bidlack
  • Lajos Szabò
  • Robin Polt
  • Edward J. Bilsky
Original Investigation

Abstract

Rationale and objectives

The present study characterized the behavioral pharmacology of a novel, mixed-action delta-selective (78:1) opioid receptor agonist, BBI-11008. This glycopeptide drug candidate was tested in assays assessing antinociception (acute, inflammatory, and neuropathic pain-like conditions) and side-effect endpoints (respiratory depression and drug self-administration).

Results

BBI-11008 had a 78-fold greater affinity for the delta opioid receptor than the mu receptor, and there was no binding to the kappa opioid receptor. BBI-11008 (3.2–100; 10–32 mg kg−1, i.v.) and morphine (1–10; 1–3.2 mg kg−1, i.v.) produced antinociceptive and anti-allodynic effects in assays of acute thermal nociception and complete Freund’s adjuvant (CFA)-induced inflammatory pain, with BBI-11008 being less potent than morphine in both assays. BBI-11008 (1–18 mg kg−1, i.v.) had similar efficacy to gabapentin (10–56 mg kg−1, i.v.) in a spinal nerve ligation (SNL) model of neuropathic pain. In the respiration assay, with increasing %CO2 exposure, BBI-11008 produced an initial increase (32 mg kg−1, s.c.) and then decrease (56 mg kg−1, s.c.) in minute volume (MV) whereas morphine (3.2–32 mg kg−1, s.c.) produced dose-dependent decreases in MV. In the drug self-administration procedure, BBI-11008 did not maintain self-administration at any dose tested.

Conclusions

These results suggest that the glycopeptide drug candidate possesses broad-spectrum antinociceptive and anti-allodynic activity across a range of pain-like conditions. Relative to morphine or fentanyl, the profile for BBI-11008 in the respiration and drug self-administration assays suggests that BBI-11008 may have less pronounced deleterious side effects. Continued assessment of this compound is warranted.

Keywords

Antinociception Antiallodynia Respiratory depression GI transit Drug self-administration Delta opioid receptor Delta/mu opioid agonist Glycopeptide Rats Mice 

Notes

Acknowledgments

We would like to thank Drs. Mark S. Kleven and Vincent Castagné for running the primary observation (Irwin) test.

Funding information

This research was supported by a NIDA/SBIR R43 DA026653-01A1 to Biousian Biosystems, Inc. (R.P. and E.J.B.) and an NIAMS AR054975 to G.W.S.

Compliance with ethical standards

Conflict of interest

Edward J. Bilsky is co-owner of BBI. Robin Polt is co-owner of BBI.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  • Glenn W. Stevenson
    • 1
    • 2
    Email author
  • Denise Giuvelis
    • 3
  • James Cormier
    • 3
  • Katherine Cone
    • 1
  • Phillip Atherton
    • 1
  • Rebecca Krivitsky
    • 1
  • Emily Warner
    • 1
  • Brooke St. Laurent
    • 1
  • Julio Dutra
    • 1
  • Jean M. Bidlack
    • 4
  • Lajos Szabò
    • 5
  • Robin Polt
    • 5
  • Edward J. Bilsky
    • 2
    • 3
    • 6
  1. 1.Department of PsychologyUniversity of New EnglandBiddefordUSA
  2. 2.Center for Excellence in the NeurosciencesUniversity of New EnglandBiddefordUSA
  3. 3.Department of Biomedical SciencesUniversity of New England College of Osteopathic MedicineBiddefordUSA
  4. 4.Department of Pharmacology and PhysiologyUniversity of Rochester School of Medicine and DentistryRochesterUSA
  5. 5.Department of Chemistry and BiochemistryThe University of ArizonaTucsonUSA
  6. 6.Department of Biomedical Sciences College of Osteopathic MedicinePacific Northwest University of Health SciencesYakimaUSA

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