Biochemical, Oxidative, and Physiological Changes Caused by Acute Exposure of Fentanyl and Its 3 Analogs in Rodents

Abstract

Synthesis and bioefficacy of fentanyl and its 8 new 1-substituted analogs (1-8) were earlier reported by us. Of these 8 compounds, N-(1-(2-phenoxyethyl)-4-piperidinyl)propionanilide (2), N-isopropyl-3-(4-( N-phenylpropionamido)piperidin-1-yl)propanamide (5), and N- t-butyl-3-(4-( N-phenylpropionamido)piperidin-1-yl) propanamide (6) were found to be more effective and less toxic compared to fentanyl. The present study reports the acute effect of fentanyl (0.50 Median Lethal Dose (LD); intraperitoneal) and its 3 analogs (2, 5, and 6) on various biochemical and oxidative parameters in mice and various physiological parameters in rats. Blood alkaline phosphatase (1 hour and 7 days) and urea levels (1 hour) were significantly elevated by fentanyl, while alanine aminotransferase levels (1 hour) were increased by both fentanyl and analog 2 compared to the corresponding control. Increase in partial pressure of carbon dioxide and decrease in partial pressure of oxygen were also caused by fentanyl and analog 2 (1 hour). Analog 6 alone elevated malondialdehyde levels in the brain, liver, and kidney tissues (7 days). The LD of fentanyl and analogs 2, 5, and 6 were found to be 0.879, 87.88, 69.80, and 55.44 mg/kg, respectively, in rats. Significant decrease in heart rate, mean arterial pressure, respiratory rate (RR), and neuromuscular transmission was produced by fentanyl and analog 2, while analog 5 decreased the RR alone. The changes, particularly the respiratory depression, were found to be reversed by naloxone, a μ-receptor antagonist. Thereby, indicating involvement of μ-receptor mediated effects of the compounds. To conclude, all the analogs were found to be less toxic compared to fentanyl, suggesting their possible role in pain management.

Zebrafish larvae: A new model to study behavioural effects and metabolism of fentanyl, in comparison to a traditional mice model

“…34 The mechanical stimulation did not affect animals treated with the range dose 1–15 mg/kg at 245 min (Figure 2 C and D). This effect could be related to the respiratory depression seen in mice 15,35 and/or the muscle rigidity as reported in rats 36 and in cases of fentanyl users. 37…”

“…34 The mechanical stimulation did not affect animals treated with range dose 1-15 mg/kg at 245 min (Figure 2 C and D). This effect could be related to the respiratory depression seen in mice 15,35 and/or the muscle rigidity as reported in rats 36 and in cases of fentanyl users. 37 Previous studies carried out both in vivo and in vitro models 38,39 showed that fentanyl is mainly metabolized to norfentanyl by N-dealkylation at the piperidine ring; only less than 1% is converted by alkyl hydroxylation or combined N-dealkylation and hydroxylation to hydroxyfentanyl and hydroxynorfentanyl.…”

Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats

“…Prior clinical data show that high doses of morphine induce a marked but transient reduction in urinary flow rate and a robust decrease in glomerular filtration rate (Mercadante and Arcuri, 2004). Both fentanyl and carfentanil induce substantial decreases in mean arterial pressure in rodents (Wong et al, 2017;Yadav et al, 2018), and it is tempting to speculate this effect could contribute to reduction in urine output. Regardless of the mechanisms involved, we hypothesize that nonlinear accumulation of carfentanil in humans could exacerbate the inherent dangers of this ultrapotent opioid agonist.…”

OFP011 Cyclic Peptide as a Multifunctional Agonist for Opioid/Neuropeptide FF Receptors with Improved Blood–Brain Barrier Penetration

“…Blood gas analysis was conducted as described . Male mice weighing 25–30 g received subcutaneously administered saline or OFP011 and then anesthetized with isoflurane.…”