Amitifadine, a triple reuptake inhibitor, reduces self-administration of the opiate remifentanil in rats

• Published in: Psychopharmacology 2020-06, Vol.237 (6), p.1681-1689
• Main Authors: Levin, Edward D., Wells, Corinne, Hawkey, Andrew, Holloway, Zade, Blair, Graham, Vierling, Alexander, Ko, Ashley, Pace, Caroline, Modarres, John, McKinney, Anthony, Rezvani, Amir H., Rose, Jed E.
• Format: Article
• Language: English
• Subjects: Analgesia; Analgesics, Opioid - administration & dosage; Animals; Antidepressants; Aza Compounds - pharmacology; Aza Compounds - therapeutic use; Biomedical and Life Sciences; Biomedicine; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Chronic pain; Control; Dopamine; Dopamine - metabolism; Dopamine Uptake Inhibitors - pharmacology; Dopamine Uptake Inhibitors - therapeutic use; Dosage and administration; Dose-Response Relationship, Drug; Drug addiction; Drug self-administration; Female; Humans; Motivation - drug effects; Motivation - physiology; Narcotics; Neurosciences; Nicotine; Nicotine - administration & dosage; Norepinephrine; Norepinephrine - antagonists & inhibitors; Norepinephrine - metabolism; Opioids; Original Investigation; Pain - drug therapy; Pain - metabolism; Pain perception; Patient outcomes; Pharmacology/Toxicology; Psychiatry; Rats; Rats, Sprague-Dawley; Remifentanil; Remifentanil - administration & dosage; Rodents; Self Administration; Self medication; Serotonin; Serotonin - metabolism; Serotonin uptake inhibitors; Serotonin Uptake Inhibitors - pharmacology; Serotonin Uptake Inhibitors - therapeutic use; Stereoisomerism
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-020-05489-w

Rationale A variety of neural systems are involved in drug addiction, and some of these systems are shared across different addictive drugs. We have found several different types of drug treatments that successfully reduce nicotine self-administration. Objectives The current set of studies is the first in a series to determine if drug treatments that have been found to significantly reduce nicotine self-administration would reduce opiate self-administration. Methods Amitifadine, a triple reuptake inhibitor of dopamine, norepinephrine, and serotonin, was assessed in female Sprague-Dawley rats to determine whether it significantly reduces remifentanil self-administration with either acute or chronic treatment. Results Acutely, amitifadine doses of 5, 10, and 20 mg/kg each significantly reduced remifentanil self-administration. In a chronic study, repeated treatment with 10 mg/kg of amitifadine continued to reduce remifentanil self-administration, even after the cessation of treatment. However, amitifadine was not found to attenuate the rise in remifentanil self-administration with continued access. This study and our earlier one showed that the 10 mg/kg amitifadine dose did not significantly affect food motivated responding. Amitifadine did not attenuate remifentanil-induced antinociception as measured on the hot plate test but extended and maintained antinociceptive effects. Conclusions These studies show the promise of amitifadine as a treatment for countering opiate self-administration for adjunctive use with opioids for analgesia. Further studies are needed to determine the possible efficacy of amitifadine for combating opiate addiction or preventing it in humans during adjunctive use with opioids for chronic pain.