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GAL‐021, a novel respiratory stimulant, attenuates opioid–induced respiratory depression without compromising analgesia
Author(s) -
Baby Santhosh M,
Gruber Ryan B,
Puskovic Veljko,
Peng Sean,
Dax Scott L,
Golder Francis J,
MacIntyre D Euan,
Mannion James C
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.704.28
Subject(s) - anesthesia , morphine , medicine , opioid , respiratory system , respiratory minute volume , tidal volume , ventilation (architecture) , bolus (digestion) , pharmacology , receptor , mechanical engineering , engineering
Opioid‐induced respiratory depression (OIRD) is a common side effect of opioid analgesics and can be life‐threatening, especially during the perioperative period and sleep. Current therapy for OIRD includes administering opioid antagonists and/or decreasing subsequent opioid doses, both of which can compromise analgesia. Here, we describe a novel respiratory stimulant, GAL‐021, that increases minute ventilation (Vmin) and reverses OIRD without diminishing analgesia. GAL‐021 administered as an IV bolus (0.01 – 3 mg/kg) to anesthetized rats or by infusion (0.01 – 0.4 mg/kg/min × 60‐min) to conscious rats increased Vmin, tidal volume (VT), and respiratory frequency ( f ). In anesthetized rats, the ED50 for increasing Vmin was 140 μg/kg. In conscious rats, OIRD was induced with morphine (10 mg/kg, IV), which increased PaCO 2 and decreased Vmin, VT, f , pH, and PaO 2 for up to 2 hours. Subsequent infusion of GAL‐021 (0.03 – 0.4 mg/kg/min, IV) resulted in dose‐dependent diminution of the evoked respiratory depression for the duration of the infusion (20 min). The increase in Vmin induced by GAL‐021 was due to an increase in VT but not f . Termination of GAL‐021 infusion restored OIRD. In contrast, GAL‐021 did not diminish morphine‐induced analgesia assessed by the tail‐flick assay. These data demonstrate that GAL‐021 stimulates breathing in conscious and anesthetized rats and reverses OIRD without attenuating analgesia.