Interactions between Fentanyl and 2,5-dimethoxy-4-methylamphetamine (DOM), a 5-HT 2A Receptor Agonist, in Rhesus Monkeys Responding under a Food Versus Drug Choice Procedure

• Published in: The FASEB journal 2022-05, Vol.36 Suppl 1 (S1)
• Main Author: Maguire, David R
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.0R788

5-HT receptor agonists such as DOM enhance antinociceptive effects of opioids suggesting a 5-HT receptor agonist could be combined with an opioid to improve treatment of pain. However, it is unclear whether 5-HT receptor agonists also enhance adverse effects of opioids, including positive reinforcing effects that contribute to abuse. This study examined whether DOM alters the reinforcing effects of fentanyl in rhesus monkeys (n=5) responding under a food versus drug choice procedure. Responding on one lever delivered sucrose pellets and responding on the other lever delivered intravenous infusions. Sessions comprised 4 blocks, each with 2 forced trials, during which only one option was available, followed by 6 choice trials, during which both options were available. The unit dose of fentanyl (0.0001-0.0032 mg/kg/infusion) increased across blocks each session. In the first experiment, sessions were preceded by intravenous administration of DOM (0032-0.32 mg/kg), naltrexone (0.032 mg/kg), or heroin (0.1 mg/kg). Then, fentanyl was available for self-administration in combination with DOM in unit dose ratios (fentanyl to DOM) of 1:3, 1:10, or 1:30. Fentanyl increased choice of infusions from less than 10% of trials with the two smallest unit doses to over 80% of trials with the two larger unit doses. Naltrexone decreased choice of fentanyl, shifting the dose-effect curve rightward, and heroin increased choice of the two smallest unit doses of fentanyl. When administered before the session, DOM reduced choice of fentanyl as well as the number of trials completed. However, DOM did not alter choice or the number of trials completed when available in combination with fentanyl. Attenuation of fentanyl choice by naltrexone and enhancement of fentanyl choice by heroin demonstrate sensitivity of responding to modulation by other drugs. DOM did not appear to enhance the reinforcing effects of fentanyl whether given as a pretreatment or made available in combination with fentanyl. Although pretreatment with DOM decreased choice of fentanyl, it did so at doses that reduced trials completed, suggesting effects of DOM might have been due, at least in part, to generalized rate-decreasing effects. Taken together with previous studies, these results suggest that DOM enhances some (antinociceptive) but not other (reinforcing) effects of opioids and that combining a 5-HT receptor agonist with an opioid to treat pain would not increase potential for abuse.