Experimental assessment of the addiction liability of N-(y-aminobutyryl)-1-aza-4,7,10,13-tetraoxacyclopentadecane hydrochloride (C-3) in rats

The safe clinical use of centrally acting analgesics remains limited by the risk of tolerance, physical dependence, and addictive behavior associated with prolonged administration. Therefore, preclinical evaluation of abuse liability represents an essential component of pharmacological screening for novel analgesic compounds. The aim of this study was to experimentally assess the addictive potential of compound C-3 (N-(γ-aminobutyryl)-1-aza-4,7,10,13-tetraoxacyclopentadecane hydrochloride) by investigating reward-related behavior, tolerance development, cross-tolerance, and withdrawal manifestations in rats. The study was conducted in adult male Wistar rats (n = 7 per group). Reward properties were evaluated using the conditioned place preference (CPP) paradigm. Antinociceptive effect and tolerance were assessed in the tail-flick test following 28-day intraperitoneal administration of C-3 (1 mg/kg), while cross-tolerance was examined after morphine administration (5 mg/kg). Statistical analysis was performed using nonparametric tests (Mann–Whitney U test, Wilcoxon signed-rank test, Friedman test; p<0.05). C-3 produced a significant antinociceptive effect, increasing latency by 58.9% compared with baseline values (p<0.05). No reduction in analgesic efficacy was observed after 28 days of repeated administration, indicating absence of pharmacodynamic tolerance. In the CPP paradigm, no significant increase in time spent in the drug-paired compartment was detected; ΔT values remained within the range of normal behavioral variability (p>0.05). Discontinuation of chronic treatment did not induce hyperalgesia or clinically relevant signs of spontaneous withdrawal. Moreover, morphine responsiveness remained preserved after prolonged C-3 exposure, demonstrating absence of cross-tolerance and suggesting lack of long-term μ-opioid receptor desensitization. Collectively, these findings indicate a favorable addiction-related profile of C-3 under the studied dosing regimen. Further investigations should explore broader dose ranges and clarify receptor-mediated mechanisms underlying its pharmacological effects.