No abstract

An increasing number of opioid overdose deaths have resulted from the rising availability of both prescription and nonprescription opioids. Pharmacotherapies, such as buprenorphine and methadone, are used to treat those dependent on opioids. However, these commonly used pharmacotherapies are opioid partial agonists and agonists, so the patient remains in an opioid‐dependent state throughout treatment. Treatment requires long‐term tapering with buprenorphine or methadone, during which withdrawal symptoms can occur. These limitations show a clear need for a non‐opioid pharmacotherapy. Drugs that target the NMDA receptor have been proposed as alternatives to opioid‐targeted pharmacotherapies. The NMDA receptor is involved in the maintenance of opioid dependence and its blockade may reverse the neuroadaptive changes induced by opioid dependence. Regulation of the NMDA receptor could accelerate treatment of opioid dependency (Glass, 2011). Ketamine, an NMDA antagonist, has potential as a treatment, but has associated side effects and potential for abuse. Rapastinel is a novel drug marketed as an antidepressant, and it acts as a partial agonist of the NMDA receptor complex. The negative side effects reported with ketamine have not been reported with rapastinel (Moskal et al., 2016). Since rapastinel acts as a partial agonist and has no reported side effects, it may be a more tolerable treatment option for those dependent on opioids. Male and female adolescent (between 28 and 30 days old) Sprague‐Dawley rats were injected with morphine in increasing doses twice a day for five days (5 mg/kg/day–25 mg/kg/day) to induce opioid dependency. On day six, rats were injected with naloxone (1 mg/kg) and withdrawal signs were quantified. Rats were then given either ketamine injections (1 mg/kg) twice daily (n=12), rapastinel injections (5 mg/kg) every other day (n=14), or saline injections (n=24). On day nine, rats were again administered naloxone (1 mg/kg), and withdrawal signs were quantified to measure efficacy of ketamine and rapastinel. Rapastinel treated rats exhibited significantly fewer withdrawal signs than those treated with ketamine, which did not differ from controls. These results show that rapastinel significantly enhances recovery from opioid dependence.Support or Funding InformationFunding provided by ASPET, Duke University SURPH program, and Duke University Department of Pharmacology and Cancer BiologyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The purpose of the present study was to evaluate the efficacy of rapastinel, an allosteric modulator of NMDA receptor function, to accelerate the loss of opioid withdrawal symptoms and blunt or prevent relapse to morphine conditioned place preference (CPP) in rats. Two studies were conducted. In study 1, adult and adolescent male and female rats were treated with increasing doses of morphine (5 mg/kg, bid to 25 mg/kg bid) for 5 days. On day 6 animals were treated with naloxone (1 mg/kg) and withdrawal was assessed. They were then treated with saline or rapastinel (5 mg/kg) on days 6 and 8, and withdrawal assessed on day 9. Rapastinel treated animals exhibited significantly lower levels of withdrawal signs on day 9. No sex or age differences were observed. In Study 2, CPP for morphine was established in adult rats (males and females) by 4 daily pairings with saline and morphine (am/pm alternation). They were tested for CPP on day 5, and then treated with rapastinel (5 mg/kg) or saline daily on days 6-10 of extinction. On day 11 they received a final dose of rapastinel or saline followed by extinction. On day 12, animals received 1 mg/kg of morphine and were tested for relapse. Rapastinel did not affect extinction of CPP, but rapastinel-treated animals spent significantly less time in the previously morphine-paired side than saline-treated animals during the relapse trial. These findings of accelerated loss of withdrawal signs and blunted relapse to CPP suggest that rapastinel could provide an adjunctive therapy for opioid dependence during initiation of pharmacotherapy for opioid dependence.