TY - JOUR
T1 - Behavioral pharmacology of the mixed-action delta-selective opioid receptor agonist BBI-11008
T2 - studies on acute, inflammatory and neuropathic pain, respiration, and drug self-administration
AU - Stevenson, Glenn W.
AU - Giuvelis, Denise
AU - Cormier, James
AU - Cone, Katherine
AU - Atherton, Phillip
AU - Krivitsky, Rebecca
AU - Warner, Emily
AU - St. Laurent, Brooke
AU - Dutra, Julio
AU - Bidlack, Jean M.
AU - Szabò, Lajos
AU - Polt, Robin
AU - Bilsky, Edward J.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
KW - Antiallodynia
KW - Antinociception
KW - Delta opioid receptor
KW - Delta/mu opioid agonist
KW - Drug self-administration
KW - GI transit
KW - Glycopeptide
KW - Mice
KW - Rats
KW - Respiratory depression
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U2 - 10.1007/s00213-019-05449-z
DO - 10.1007/s00213-019-05449-z
M3 - Article
C2 - 31912192
AN - SCOPUS:85077612999
VL - 237
SP - 1195
EP - 1208
JO - Psychopharmacology
JF - Psychopharmacology
SN - 0033-3158
IS - 4
ER -