Morphine drug discrimination: A behavioral model to assess novel synthetic opioid substances

Abstract

A large number of novel psychoactive substances including opioid‐like compounds have appeared on the illicit market in the past decade. Several substances structurally related to fentanyl are being abused alone and in combination with other drugs (e.g., heroin and/or cocaine), resulting in overdoses at an alarming rate. There is a paucity of information about the pharmacology of these novel synthetic substances. In this study, we evaluated the opioid‐like stimulus effects of crotonyl fentanyl, thiophene fentanyl, benzodioxole fentanyl, and methoxyacetyl fentanyl, four newly identified substances structurally related to fentanyl. We compared the potencies of these new substances to schedule II opioid analgesics such as fentanyl and morphine using a preclinical abuse liability assessment model called drug discrimination. We also studied the susceptibility of the stimulus effects of these test drugs to antagonism by the opioid antagonist naltrexone, a drug used in patients to reverse the overdose effects of heroin and fentanyl. Using a two‐lever operant experimental chamber under a fixed ratio‐10 schedule for food delivery, rats (Sprague Dawley) were trained to discriminate between 3.2 mg/kg morphine and saline, subcutaneously. We evaluated saline and multiple doses of morphine, fentanyl, crotonyl fentanyl, thiophene fentanyl, benzodioxole fentanyl, and methoxyacetyl fentanyl. Crotonyl fentanyl, thiophene fentanyl, and methoxyacetyl fentanyl, similar to morphine and fentanyl, fully substituted for the morphine discriminative stimulus and decreased response rates with slightly differing potencies. Benzodioxole fentanyl failed to produce significant morphine‐like responding or rate‐decreasing effects at any dose although testing was limited by solubility issues. Crotonyl fentanyl, thiophene fentanyl, and methoxyacetyl fentanyl were blocked by naltrexone indicating that mechanisms of action of these three drugs are similar to that of morphine and fentanyl. The opioid‐like discriminative stimulus effects of crotonyl fentanyl, thiophene fentanyl, and methoxyacetyl fentanyl indicate that subjective effects and abuse liability of these three novel substances are likely to be similar to that of morphine and fentanyl.Support or Funding InformationDJD‐17‐HQ‐P‐0646This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.