Effects of Cebranopadol on Cocaine-induced Hyperactivity and Cocaine Pharmacokinetics in Rats

Abstract

Cebranopadol is known as a highly potent analgesic. Recent studies also demonstrated that administration of cebranopadol significantly decreased cocaine self-administration and significantly reduced cue-induced cocaine-seeking behaviors in rats. However, it was unclear whether these interesting behavioral observations are related to any potential effects of cebranopadol on cocaine pharmacokinetics or cocaine-induced hyperactivity. In principle, a promising therapeutic candidate for cocaine dependence treatment may alter the cocaine pharmacokinetics and/or attenuate cocaine-induced reward and hyperactivity and, thus, decrease cocaine self-administration and reduce cue-induced cocaine-seeking behaviors. In this study, we examined possible effects of cebranopadol on cocaine pharmacokinetics and cocaine-induced hyperactivity for the first time. According to our animal data in rats, cebranopadol did not significantly alter the pharmacokinetics of cocaine. According to our more extensive locomotor activity testing data, cebranopadol itself also dose-dependently induced hyperactivity in rats at doses higher than 50 µg/kg. Cebranopadol at a low dose of 25 µg/kg (p.o.) did not induce significant hyperactivity itself, but significantly potentiated cocaine-induced hyperactivity on Days 4 to 7 after the repeated daily dosing of the drug.

Cebranopadol as a Novel Promising Agent for the Treatment of Pain

“…In these experiments, no significant effects of cebranopadol on cocaine kinetics were detected [40]. However, despite the fact that cebranopadol decreases cocaine self-intake, Wei et al indicated that cebranopadol at the dose of 50 ug/kg potentiated cocaine-induced hyperactivity [40]. According to Shen et al, the mechanism of action of cebranopadol on cocaine self-administration is based on two possibly independent mechanisms involving NOP and the classical opioid receptor, as only the simultaneous blockade of both these pathways determines the inhibition of cocaine self-intake [39].…”

“…Subsequently, Wei et al examined the influence of cebranopadol on cocaine kinetics. In these experiments, no significant effects of cebranopadol on cocaine kinetics were detected [40]. However, despite the fact that cebranopadol decreases cocaine self-intake, Wei et al indicated that cebranopadol at the dose of 50 ug/kg potentiated cocaine-induced hyperactivity [40].…”

Attenuated G protein signaling and minimal receptor phosphorylation as a biochemical signature of low side-effect opioid analgesics

“…Interestingly, clinically used buprenorphine which shows partial agonism at both MOP and NOP, has a phosphorylation profile similar to AT-201 wherein it stimulates only S375 phosphorylation at MOP but none at NOP 20 , 21 Cebranopadol showed a more ‘MOP-dominant’ profile and partial to high efficacy at NOP in G protein signaling assays. Despite its clinical efficacy in pain, cebranopadol has been reported to produce reinforcing effects in rats, nonhuman primates and produced drug liking in human clinical trials 48 , 58 , 59 . Correspondingly, it elicited strong multi-site phosphorylation at MOP and weak NOP phosphorylation at S346.…”

Metabolites profiling and pharmacokinetics of troxipide and its pharmacodynamics in rats with gastric ulcer

“…The NCGIG rats and GUGIG rats were weighed and given a single dose of 20 mg/kg, 40 mg/kg, or 60 mg/kg troxipide (10 mL/kg) via intragastric administration. The rat blood collection method used in our study was performed according to ICH guidelines and the guidelines of the Nonclinical Pharmacokinetics of Medicinal Products by National Medical Products Administration (NMPA) and was based on previous reports and our preliminary studies 90 – 92 . The approximately 0.3 mL of plasma was collected from the orbital venous plexus of the NCGIG and GUGIG rats before administration and 15, 30, 60, 120, 180, 240, 360, 480, 600, 720, 1,440, 2,160, 2,880 min after administration .…”