Analgesic Effects of Ketamine Versus Its Novel Analogue, SN35210: Insights from Tail-flick Responses and Brain Activation in Rats Mitchell Head , Anica Klockars; Pawel K. Olszewski; Logan J. Voss; Jamie W. Sleigh; Martyn G. Harvey (Science and Engineering, University of Waikato, Hamilton, New Zealand) C5
Ketamine is a common anaesthetic that reduces the excitatory action of glutamate and induces loss of consciousness. 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 advantageous effects are potentiated. The present project, utilizing adult Sprague-Dawley rats as an animal model, focused on examining functional properties of a novel ester-analogue of ketamine, SN35210, whose potentially beneficial profile had been suggested by preliminary studies. First, by monitoring tail-flick responses to heat, we found that intravenous administration of SN35210 produced analgesia of similar depth to that of ketamine. However, SN35210 elicited significantly extended duration of analgesia by approximately 100%, when compared to ketamine. We then sought to examine whether the differential tail-flick responses after intravenous ketamine versus SN35210 are reflected by a different pattern of neuronal activation in brain areas critical for analgesia. We employed immunohistochemical detection of an immediate-early gene product, cFos, as a marker of neuronal activity. This showed that intravenous administration of ketamine and SN35210 generate similar cFos activation in several areas including the insular cortex and area postrema. However, significantly different activation was observed in hypothalamic nuclei such as the supraoptic nucleus, in the core and shell of the nucleus accumbens, and in the basolateral amygdala. The observed differences in duration of analgesia produced by each drug may therefore be attributable to differences detected in brain activation patterns. We conclude that SN35210 produces an analgesic effect of longer duration, but of similar depth to that of ketamine, and that the distinct brain network activation in response to each of these drugs might underlie the differential analgesic profiles of these compounds.