Effect of novel ketamine-analogue R5 on brain activation and select behavioural parameters

Abstract

Ketamine is a common anaesthetic that works through complex neural mechanisms, including multiple molecular and circuitry targets. Importantly, it promotes analgesia, though it also induces undesirable effects, such as agitation, disorientation, hallucinations and nausea. Thus, there is an ongoing search for novel ketamine analogues that influence a similar repertoire of brain targets as ketamine, whose beneficial effects are potentiated. The present project, utilizing rats as an animal model, focused on examining functional properties of the ester-analogue of ketamine, R5, whose potentially beneficial profile had been suggested by preliminary studies. First, brain activation patterns following R5 compared to ketamine (and another ester-analogue control compound, R1) were assessed by employing immunohistochemical detection of an immediate-early gene product, c-Fos. R5 produced a somewhat similar pattern of activity as ketamine, whereas more profound differences in c-Fos were detected after R1. It was particularly striking in areas related to pain and addiction, including the anterior insular cortex (AIC) and paraventricular nucleus (PVN). Therefore, in the subsequent set of experiments, effects of R5 on pain- and addiction-related behavioral parameters were assessed in rats injected with R5 intracerebroventricularly (ICV) or intraparenchymally. It was found that BaCl attenuated ICV R5-induced analgesia. AIC administration of R5 produced modest analgesia in the tail-flick test. Finally, PVN R5 reduced naltrexone-precipitated exercise-induced withdrawal. In sum, R5 shows an analgesic effect similar to ketamine, most likely by targeting a similar subset of brain sites, which suggests that this particular ester-analogue can be considered as a good candidate for conceptualizing future pain management strategies.