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A Novel, Long‐Lasting μ Opioid Receptor Antagonist Prevents and Reverses the Respiratory‐Depressant Effects of Heroin in Rhesus Monkeys
Author(s) -
Gerak Lisa R,
Maguire David R,
Woods James H,
Husbands Stephen,
France Charles P
Publication year - 2018
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.2018.32.1_supplement.lb608
Subject(s) - heroin , naltrexone , (+) naloxone , depressant , opioid , pharmacology , opioid antagonist , narcotic antagonist , medicine , morphine , respiratory system , anesthesia , antagonist , opioid overdose , respiratory rate , drug , receptor , heart rate , blood pressure
Opioid overdose continues to be a serious public health problem in the US with fatal overdose occurring in at least 115 Americans every day. Naloxone (Narcan®) is increasingly available to reverse respiratory depression, the fatal effect of opioids; however, its relatively short duration of action limits the protection it can provide. SH‐1 is a novel opioid antagonist that has a longer duration of action than other opioid antagonists, including naloxone and naltrexone. The current study examined the ability of SH‐1 to prevent and reverse the respiratory‐depressant effects of heroin using head plethysmography to monitor minute volume (V E ) in 4 monkeys breathing air. First, SH‐1 was given before heroin to determine whether it would prevent respiratory depression. The duration of action of SH‐1 was assessed by generating heroin dose‐effect curves at various times (1, 2, 4, and 8 days) after administration of 0.32 mg/kg SH‐1; these effects of SH‐1 were compared to those of naltrexone (0.032 mg/kg). The ability of SH‐1 to reverse the respiratory‐depressant effects of heroin was determined by giving a single injection of heroin to decrease minute volume (V E ) followed 30 min later by an injection of either saline or 0.32 mg/kg SH‐1. In the absence of drug (control), average V E (± SEM) was 1531±113 ml/min. Heroin dose dependently decreased V E , and the potency of heroin varied across monkeys with the dose needed to decrease V E to <70% of control ranging from 0.1–1 mg/kg. When given before heroin, SH‐1 and naltrexone prevented the respiratory‐depressant effects of heroin, shifting the heroin dose‐effect curve 6‐fold rightward in each monkey. SH‐1 continued to attenuate the respiratory‐depressant effects of heroin for at least 4 days after administration whereas naltrexone antagonized heroin only on the day it was administered. When heroin decreased V E to <70% of control, subsequent administration of SH‐1 reversed these respiratory‐depressant effects within 30 min. Thus, SH‐1 can both prevent and reverse the respiratory‐depressant effects of heroin and these effects last longer than those of naltrexone. Because of its sustained effects, the novel compound SH‐1 might provide greater protection against the fatal respiratory‐depressant effects of opioids, thereby improving treatment of opioid overdose. Support or Funding Information Supported by NIH (R01DA005018) and the Welch Foundation (AQ‐0039). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .