Physiological effects of fentanyl analogs found in recreational drug markets

Abstract

<b>Abstract ID 17435</b> <b>Poster Board 106</b> Structural analogs of fentanyl are increasingly associated with human overdose fatalities, yet little is known about the pharmacology of these compounds. Here we studied the physiological effects of fentanyl analogs that have appeared in recreational drug markets worldwide. Six male Sprague-Dawley rats received surgically implanted telemetry transmitters for the measurement of blood pressure (BP), heart rate (HR), locomotor activity, and body temperature. Rats in their home cages were placed onto telemetry receivers for 3 h each weekday, with subcutaneous (s.c.) drug or vehicle injections administered twice weekly. We also examined the effects of fentanyl and its analogs in assays measuring opioid receptor binding in rat brain tissue, and inhibition of cAMP accumulation in cells transfected with mu-opioid receptors (MOR). The telemetry results revealed that all fentanyl analogs produce dose-dependent increases in BP, HR, activity, and temperature, but the potency of the compounds varied substantially. The calculated ED₅₀ values for inducing hypertensive effects showed that fentanyl was most potent (0.01 mg/kg), followed closely by furanylfentanyl (0.014 mg/kg), cyclopropylfentanyl (0.028 mg/kg), and butyrylfentanyl (0.081 mg/kg). Acetylfentanyl (0.166 mg/kg) was slightly less potent than butyrylfentanyl, but had a potency similar to the illicit opioid heroin (0.215 mg/kg). Valerylfentanyl was the least potent analog by far (2.071 mg/kg), which had potency similar to the opioid analgesic morphine (2.689 mg/kg). Radioligand binding assays demonstrated that all fentanyl analogs displayed higher affinity for mu-opioid receptors (MOR) over delta and kappa sites, and all of the drugs induced MOR-mediated inhibition of cAMP accumulation. Importantly, the rank order of potency for the fentanyl analogs to increase BP was similar to the rank order of affinity at MOR and potency for inhibiting cAMP. We also tested the ability of opioid receptor antagonists to alter the in&nbsp;vivo effects of fentanyl and butyrylfentanyl. The centrally active opioid antagonist, naltrexone (0.3 mg/kg, s.c.), blocked all of the effects of both drugs, whereas the peripherally restricted opioid antagonist, naloxone methiodide (2.0 mg/kg, s.c.), partially reduced only the BP and HR effects. These findings indicate that locomotor and temperature effects induced by fentanyl and its analogs are centrally mediated, while cardiovascular effects may involve peripheral mechanisms. In conclusion, we demonstrate that fentanyl analogs evoke physiological responses that are similar to fentanyl itself, and these responses are most likely mediated via agonist activity at MOR. With the exception of valerylfentanyl, which is a very low potency agonist, fentanyl analogs are much more potent than morphine, suggesting these analogs may pose serious health risks to users. This work was supported by NIDA/NIH.