A slow onset of action has been hypothesized to weaken the reinforcing effects of drugs. The present study evaluated this hypothesis with slow-onset cocaine analogs, WIN 35428, RTI 31, and RTI 51. When cocaine or a cocaine analog was made available to rhesus monkeys (n ¼ 4 or 5) for self-administration under a progressive-ratio (PR) schedule with a 1-h time-out between injections, all the drugs functioned as positive reinforcers. The maximum number of injections was in the order of cocaine4WIN 354284RTI 314RTI 51. In in vivo binding in rat striatum, equipotent doses of cocaine, WIN 35428, RTI 31, and RTI 51 were estimated to displace 25% of [ 3 H]WIN 35428 binding at the dopamine transporters (DAT), respectively, 5.8, 22.4, 30.8, and 44.1 min after the intravenous injection. Further, relative reinforcing efficacy was correlated with rate of DAT binding such that slower displacement of [ 3 H]WIN 35428 was associated with a weaker reinforcing effect. In in vitro binding in monkey brain tissue, the cocaine analogs had higher affinity for monoamine transporter sites, but similar affinity ratios of 5-HTT/DAT, compared to cocaine. Lastly, RTI 31 was shown to function as a positive reinforcer in drug-naïve rhesus monkeys under a fixed-ratio 1 schedule. Collectively, the data support the hypothesis that a slow onset at the DAT is associated with reduced reinforcing efficacy of DAT ligands. The data under both the PR and FR schedules, however, suggest that a slow onset at the DAT influence reinforcing effect only to a limited extent.

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This study explores the therapeutic efficacy of heparin-based hydrogel micropatches containing human adipose-derived stem cells (hASCs) in treating neuropathic pain caused by nerve damage. Our results showed that hASCs exhibited neuroregenerative and pain-relieving effects when used with heparin-based hydrogel micropatches in the neuropathic pain animal model. The use of this combination also produced enhanced cell viability and nerve regeneration. We conducted various neurological behavioral tests, dynamic plantar tests, histological examinations, and neuroelectrophysiological examinations to confirm the therapeutic effect. Our findings suggest that this approach could maximize therapeutic efficacy and improve the quality of life for patients suffering from neuropathic pain.