Program

PO1-1-70

The novel, pseudo-irreversible mu opioid receptor antagonist SH-1 attenuates the reinforcing and respiratory-depressant effects of heroin in rhesus monkeys

[Speaker] David R Maguire:1
[Co-author] Lisa R Gerak:1, James H Woods:1, Stephen M Husbands:2, Alex Disney:2, Charles P France:1
1:Pharmacology, University of Texas Health Science Center at San Antonio, USA, 2:Pharmacy and Pharmacology, University of Bath, UK

Aim. Opioid abuse is a serious public health challenge, despite the availability of medications that are effective in some patients (naltrexone, buprenorphine, and methadone); thus, there is a need for more and better treatments. This study explores the therapeutic potential of a novel, pseudo-irreversible, and highly selective mu opioid receptor antagonist (SH-1) as a treatment for opioid abuse and overdose by examining its capacity to attenuate the reinforcing and respiratory-depressant effects of heroin in rhesus monkeys.

Methods. One group of monkeys (n=4) responded for i.v. infusions of heroin (0.0032 mg/kg/infusion) or cocaine (0.032 mg/kg/infusion) under a fixed-ratio 30 schedule of reinforcement. Naltrexone (0.0032-0.032 mg/kg; 15-min pretreatment) or SH-1 (0.032-0.32 mg/kg; 60-min pretreatment) were administered prior to the session. In another group (n=3), the respiratory-depressant effects of heroin, administered alone (0.032-1.0 mg/kg) and after administration of 0.32 mg/kg SH-1, were determined using plethysmography.

Results. Heroin and cocaine maintained high rates of responding. Naltrexone dose-dependently decreased responding for heroin during the session immediately following its administration, with responding for heroin returning to baseline levels the next day. SH-1 also dose-dependently decreased responding for heroin during the session immediately following its administration; however, responding for heroin remaining decreased for up to 8 days after a single administration. Doses of naltrexone and SH-1 that significantly decreased responding for heroin did not affect responding for cocaine. In monkeys breathing air, heroin dose-dependently decreased respiration to 70% of control at the largest dose tested. Pretreatment with SH-1 attenuated the respiratory-depressant effects of heroin, shifting the heroin dose-effect curve 6-10 fold rightward 2 days after SH-1 administration; this attenuation was no longer evident 8 days after SH-1 administration.

Conclusions. Naltrexone and SH-1 attenuated heroin but not cocaine self-administration and heroin-induced respiratory depression, consistent with their actions as opioid receptor antagonists. The very long lasting effects of SH-1 are likely due to its pseudo-irreversible binding to mu opioid receptors. To the extent that SH-1 can selectively attenuate the positive reinforcing and respiratory-depressant effects of opioids for prolonged periods, this novel drug could be superior to currently available treatments for opioid abuse and overdose.
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