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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

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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.

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Acknowledgments

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

Funding

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.

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Authors and Affiliations

  1. Department of Psychology, University of New England, Biddeford, ME, 04005, USA

    Glenn W. Stevenson, Katherine Cone, Phillip Atherton, Rebecca Krivitsky, Emily Warner, Brooke St. Laurent & Julio Dutra

  2. Center for Excellence in the Neurosciences, University of New England, Biddeford, ME, USA

    Glenn W. Stevenson & Edward J. Bilsky

  3. Department of Biomedical Sciences, University of New England College of Osteopathic Medicine, Biddeford, ME, 04005, USA

    Denise Giuvelis, James Cormier & Edward J. Bilsky

  4. Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA

    Jean M. Bidlack

  5. Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ, 85721, USA

    Lajos Szabò & Robin Polt

  6. Department of Biomedical Sciences College of Osteopathic Medicine, Pacific Northwest University of Health Sciences, Yakima, WA, 98901, USA

    Edward J. Bilsky

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  1. Glenn W. Stevenson
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Correspondence to Glenn W. Stevenson.

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

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Stevenson, G.W., Giuvelis, D., Cormier, J. et al. 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. Psychopharmacology 237, 1195–1208 (2020). https://doi.org/10.1007/s00213-019-05449-z

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