and reduced blockade of NMDA glutamatergic receptors.19 This later mechanism would then suggest that S-ketamine and S-hydroxynorketamine act at different receptor systems to induce analgesia. Zanos et al.6 showed indeed that (2R,6R)-hydroxynorketamine, but not ketamine, acts at the non-NMDA glutamate -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Moreover, a recent study from Bonaventura et al.,19 showed that (2R,6R)- hydroxynorketamine displays minimal brain uptake and rapid clearance from the brain, without any affinity for opioid receptors or any other known ketamine targets. Evidently, we need to consider the stereoselective effects of ketamine’s metabolites. We argue therefore that, similar to S-norketamine, S-hydroxynorketamine needs to be administered to humans, in future studies to quantify its analgesic effect. Drug high vs. analgesia For drug high, a dose dependent S-ketamine effect was observed (Figure 3.4A,B), without any contribution from its metabolites. Relative to the S-ketamine antinociception, S-ketamine was about 3-5 times more potent in producing its drug high effects with a C50 (S-ketamine concentration causing a drug high of 5 on an 11-point scale from 0 to 10) of 0.31 nmol/ml. Interestingly, earlier studies showed that the racemic ketamine C50 for drug high is at least a factor 2 greater than that of S-ketamine, indicative of a greater S-ketamine potency compared to the R-isomer and the racemic mixture in producing drug high effects with some studies finding that R-ketamine does not produce any psychotypical effects.19,20 Drug high effects were predominantly present during the analgesic period, suggestive of a connection between drug high and pain relief. A connection or association between the various ketamine endpoints such as analgesia and its psychotomimetic effects has been a matter of debate and has recently been refuted.20,21,22 However, the current data set and earlier studies from our laboratory support an intricate association between analgesia and psychotomimetic side effects.20 What this means is still unclear. It may relate to a similar site of action within the brain, or more probably, a connection between distinct brain areas that fire together upon exposure to ketamine. The latter would cause similar dynamics of the response (i.e. with similar onset/offset times), although potency between the two endpoints may differ. We plan further studies to increase our insights into this matter. 58
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