The Study of Chronic Methadone in Non‐Human Primates

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Previous results from our laboratory demonstrated a reduction in the ability of lower efficacy but not high efficacy agonists to provoke 1) reinstatement of drug‐seeking behavior and 2) antinociception, in buprenorphine‐maintained squirrel monkeys. However, the role of drug‐efficacy in these effects of opioids in methadone‐maintained subjects is currently unknown. Methadone has proven to be difficult to examine in preclinical research because it can produce tissue damage when given repeatedly by intramuscular (I.M.) or subcutaneous (S.C.) administration. For this reason, methadone is most commonly administered as an oral (P.O.) solution. The current experiments were conducted to investigate the time course of effects of P.O. vs. I.M. methadone in squirrel monkeys in preparation for studies involving chronic methadone administration.To efficiently characterize the time course of effects, we concurrently determined the effects of methadone on both the latency to remove the tail from warm water (antinociception) and food‐maintained behavior (response rate disruption) in squirrel monkeys. The effects of a single dose of either 1.8 mg/kg P.O. (in a sweetened solution) or 0.56 mg/kg I.M. methadone were tested at 15 and 30 mins, and 1, 2, 4, 8 and 24 hrs following administration. At each time point, stimulus lights were illuminated to signal the beginning of a test component. During each test component, completion of a 10‐response fixed‐ratio initiated food delivery and a 30‐sec short timeout (STO) during which stimulus lights were off and tail withdrawal latency from 50, 52 and 55°C water was measured. When components were more than 30 mins apart, subjects were returned to the home cage between components.The peak effect of P.O. methadone was seen at 2hrs for both antinociception and response rate disruption. At 2 hrs, tail withdrawal latencies from 50, 52 and 55°C water were 6.79 ± 1.97, 5.27 ± 1.94 and 3.66 ± 1.68, respectively, and response rates were 0.92 ± 0.38. Tail withdrawal latencies from 52 and 55°C water and response rates returned to baseline at 8hrs (1.86 ± 0.30 s, 1.32 ± 0.16 s, and 3.02 ± 0.79 resp/s, respectively), while tail withdrawal latency from 50°C water returned to baseline at 24hrs (1.63 ± 0.29 s). The peak effect of I.M. methadone was seen at 30 mins for antinociception and response rate disruption. At 30 mins, tail withdrawal latencies from 50, 52 and 55°C water were 10.0 ± 0.02, 6.74 ± 1.89, 5.01 ± 1.74, respectively, and response rates were 0.35 ± 0.35 resp/s. Tail withdrawal latencies from all water temperatures and response rates returned to baseline at 4 hrs (1.51 ± 0.22 s, 1.30 ± 0.05 s, 1.31 ± 0.17 s and 2.71 ± 0.29 resp/s, respectively).These findings suggest P.O. methadone has a longer onset and duration of action than I.M. methadone. Furthermore, this study confirms that methadone can be administered orally to non‐human primates, thereby avoiding local toxicity caused by repeated I.M methadone administration. Finally, these findings serve as preliminary data to study the effects of chronic methadone on opioid‐induced reinstatement of drug‐seeking behavior. Further experiments are currently underway.Support or Funding InformationSupported by NIDA Grant DA035857This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.