Effects of novel fentanyl derivatives in rats trained to discriminate morphine.

Novel substances structurally related to fentanyl are used alone or in combination with other drugs, resulting in toxicity and overdoses. As limited information is available about the pharmacology of these novel fentanyl derivatives, we evaluated the capacity and potency of the parent compound fentanyl and thirteen fentanyl derivatives to produce morphine-like discriminative stimulus effects. Using a two-lever, drug discrimination procedure, Sprague-Dawley rats were trained to discriminate between injections of 3.2 mg/kg morphine and saline under a fixed ratio-10 schedule for food delivery. All fentanyl and fentanyl derivatives, with the exception of benzodioxole fentanyl, fully substituted for the morphine discriminative stimulus with the following order of potency: 2'-fluoro ortho-fluorofentanyl > ortho-fluorofentanyl > fentanyl > cyclopropyl fentanyl > ortho-methylmethoxyacetyl fentanyl > thiophene fentanyl > crotonyl fentanyl > meta-fluorobutyryl fentanyl > methoxyacetyl fentanyl > 3-furanyl fentanyl >4'-methyl acetyl fentanyl > para-methoxybutyryl fentanyl > morphine > phenyl fentanyl. Co-administration of a single dose of naltrexone failed to block the morphine-like discriminative stimulus effects of 2-fluoro ortho-fluorofentanyl, ortho-fluorofentanyl, and cyclopropyl fentanyl suggesting that these three compounds may require higher doses of naltrexone for antagonism. These data suggest that the lethal effects of potent fentanyl compounds may be more difficult to reverse with opioid antagonists administered either at the same time or after the administration of potent fentanyls. Crotonyl fentanyl, thiophene fentanyl, meta-fluorobutyryl fentanyl, cyclopropyl fentanyl, 3-furanyl fentanyl, and para-methoxybutyryl fentanyl were blocked by naltrexone to varying degrees indicating that mechanisms of action and time-course of these derivatives are like that of morphine and fentanyl.