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. Stevenson, 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1195-1208
Number of pages14
JournalPsychopharmacology
Volume237
Issue number4
DOIs
StatePublished - Apr 1 2020

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

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    Stevenson, G. W., Giuvelis, D., Cormier, J., Cone, K., Atherton, P., Krivitsky, R., Warner, E., St. Laurent, B., Dutra, J., Bidlack, J. M., Szabò, L., Polt, R., & Bilsky, E. J. (2020). 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(4), 1195-1208. https://doi.org/10.1007/s00213-019-05449-z