Abstract
Nitric oxide (NO) is involved in acute μ-opioid receptor (MOR) desensitization in the locus coeruleus (LC) and in the neuroadaptations following chronic morphine administration. However, the role of NO and NO-derived reactive oxygen species (ROS) in the development of cellular tolerance to different opioids remains unclear. Herein, we examined the effect of the selective neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI; 30 mg/kg/12 h, i.p.) and the antioxidants Trolox + ascorbic acid (TX+AA; 40 and 100 mg/kg/day, respectively, i.p.) and U-74389G (10 mg/kg/day, i.p.) on the development of cellular tolerance induced by morphine, methadone and fentanyl. For induction of morphine tolerance, rats were treated subcutaneously with a slow release emulsion containing free base morphine (200 mg/kg, 3 days). For methadone (60 mg/kg/day, 6 days) and fentanyl (0.2 mg/kg/day, 7 days), tolerance was induced by s.c. implantation of osmotic pumps. Concentration-effect curves for the inhibitory effect of Met5-enkephalin (ME; 0.05-12.8 μM, 2x, 1 min) on the firing rate were performed by single-unit extracellular recordings of LC neurons from rat brain slices. Morphine, methadone and fentanyl treatments shifted to the right concentration-effect curves for ME and increased the EC50 by 2-4 folds. Co-administration of TX+AA or U-74389G in morphine-treated animals prevented the development of tolerance in LC neurons. Conversely, co-treatments with U-74389G or 7-NI failed to affect the induction of cellular tolerance after methadone or fentanyl treatments. Our results suggest that MOR agonists with different intrinsic efficacies cause variable degrees of cellular tolerance in LC cells. Moreover, NO/ROS pathways are differentially involved in opioid tolerance after prolonged treatments with morphine, methadone and fentanyl.
Highlights
IntroductionMethadone or fentanyl are among the most common clinically used opioid agonists
Morphine, methadone or fentanyl are among the most common clinically used opioid agonists
nitric oxide (NO) is produced by the neuronal NO synthase and targets the heme group of guanylate cyclase, which elevates 3’,5’-cyclic guanosine monophosphate concentrations
Summary
Methadone or fentanyl are among the most common clinically used opioid agonists. Subchronic treatment with morphine (200 mg/kg, s.c., 3 days) induced a strong degree of tolerance in the LC, which was revealed by a rightward shift in the concentration-effect curves for ME and an increase in the EC50 of about 4 fold, as compared to the corresponding sham group (p < 0.005). Chronic treatment with fentanyl (0.2 mg/kg/day, s.c., 7 days) caused a rightward shift in the concentration-effect curves for ME with an increase of the EC50 of about 3 fold, as compared to the corresponding sham group (p < 0.005). These results indicate that morphine, methadone and fentanyl induce different degrees of tolerance to the inhibitory effect of ME in LC neurons. It can be hypothesized that differences between morphine, methadone and fentanyl in their ability to induce receptor internalization and recycling (Alvarez et al, 2002; Virk and Williams, 2008) may contribute, at least in part, to the different degrees of cellular tolerance observed in this study
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
