Lipophilic analogues of D-cysteine prevent and reverse physical dependence to fentanyl in male rats

Abstract

We examined whether co-injections of the cell-permeant D-cysteine analogues, D-cysteine ethyl ester (D-CYSee) and D-cysteine ethyl amide (D-CYSea), prevent acquisition of physical dependence induced by twice-daily injections of fentanyl, and reverse acquired dependence to these injections in freely-moving male Sprague Dawley rats. Injection of the opioid receptor antagonist, naloxone HCl (NLX, 1.5 mg/kg, IV), elicited a series of withdrawal phenomena that included cardiorespiratory and behavioral responses, and falls in body weight and body temperature, in rats that received 5 or 10 injections of fentanyl (125 μg/kg, IV), and the same number of vehicle co-injections. Regarding the development of physical dependence, the NLX-precipitated withdrawal phenomena were markedly reduced in fentanyl-injected rats that had received co-injections of D-CYSee (250 μmol/kg, IV) or D-CYSea (100 μmol/kg, IV), but not D-cysteine (250 μmol/kg, IV). Regarding reversal of established dependence to fentanyl, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 μg/kg, IV) was markedly reduced in rats that received co-injections of D-CYSee (250 μmol/kg, IV) or D-CYSea (100 μmol/kg, IV), but not D-cysteine (250 μmol/kg, IV), starting with injection 6 of fentanyl. This study provides evidence that co-injections of D-CYSee and D-CYSea prevent the acquisition of physical dependence, and reverse acquired dependence to fentanyl in male rats. The lack of effect of D-cysteine suggests that the enhanced cell-penetrability of D-CYSee and D-CYSea into cells, particularly within the brain, is key to their ability to interact with intracellular signaling events involved in acquisition to physical dependence to fentanyl.

L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats

“…Three groups of rats received a jugular vein catheter of PE-10 connected to PE-50 ( Intramedic; Becton & Dickinson, Franklin Drive, NJ, USA ) under 2–3% isoflurane anesthesia, to allow injections of test agents 36 . All rats received an intraperitoneal injection of the non-steroidal anti-inflammatory analgesic, carprofen (20 mg/kg) immediately post-surgery and again 24 later.…”

“…One hour before co-injections 5 or 10 were to be given (as described above), rats were placed into individual whole body plethysmography chambers to record ventilatory parameters 36 . The free end of the exteriorized venous catheter was connected to a swivel assembly housed in the lid of the plethysmography chamber and after 60 min acclimatization, the rats received co-injections 5 or 10 and after 90 min they received an injection of NLX (1.5 mg/kg, IV).…”

“…The free end of the exteriorized venous catheter was connected to a swivel assembly housed in the lid of the plethysmography chamber and after 60 min acclimatization, the rats received co-injections 5 or 10 and after 90 min they received an injection of NLX (1.5 mg/kg, IV). The number of apneas of greater than 1.5 s in duration were determined by internal FinePointe software (DSI, Harvard Bioscience, Inc., St. Paul, MN) 36 .…”

“…Groups of rats (n = 9 rats per group) were implanted with a jugular vein catheter to inject drugs and a catheter into a femoral artery to continuously record mean arterial blood pressure (MAP) and heart rate 36 . The rats were given 5 days to recover from surgery.…”

“…The fentanyl dose-regime consisting of twice daily intravenous injections of 125 μmol/kg was based on daily doses used by others 35 . The behavioral, cardiorespiratory, thermoregulatory and body weight changes were chosen on the basis of previous studies determining the scope and types of withdrawal phenomena 36 .…”