Abstract
BackgroundKetamine ester analogs, SN 35210 and SN 35563, demonstrate different pharmacological profiles to ketamine in animal models. Both confer hypnosis with predictably rapid offset yet, paradoxically, SN35563 induces a prolonged anti-nociceptive state. To explore underlying mechanisms, broad transcriptome changes were measured and compared across four relevant target regions of the rat brain.ResultsSN 35563 produced large-scale alteration of gene expression in the Basolateral Amygdala (BLA) and Paraventricular Nucleus of the Thalamus (PVT), in excess of 10x that induced by ketamine and SN 35210. A smaller and quantitatively similar number of gene changes were observed in the Insula (INS) and Nucleus Accumbens (ACB) for all three agents. In the BLA and PVT, SN 35563 caused enrichment for gene pathways related to the function and structure of glutamatergic synapses in respect to: release of neurotransmitter, configuration of postsynaptic AMPA receptors, and the underlying cytoskeletal scaffolding and alignment.ConclusionThe analgesic ketamine ester analog SN 35563 induces profound large-scale changes in gene expression in key pain-related brain regions reflecting its unique prolonged pharmacodynamic profile.
Highlights
Ketamine ester analogs, SN 35210 and SN 35563, demonstrate different pharmacological profiles to ketamine in animal models
Behavioural metrics Infusion of all study drugs produced hypnosis characterised by Loss of Righting Reflex (LORR), and blunted responses to external stimuli
Total drug dosing to 45 min was ketamine 95.5 mg/kg, SN 35210 (R1) 229.8 (13.2) mg/kg, and SN 35563 (R5) 251.5 (9.3) mg/kg
Summary
SN 35210 and SN 35563, demonstrate different pharmacological profiles to ketamine in animal models. Both confer hypnosis with predictably rapid offset yet, paradoxically, SN35563 induces a prolonged anti-nociceptive state. Given ketamine’s complex pharmacologic profile it is perhaps unsurprising that the underlying mechanisms of its Compared to ketamine, two recently developed ketamine esters – SN 35210 (subsequently referred to as R1) and SN 35563 (R5) – demonstrate a shorter recovery time and absent psychotomimesis following hypnosis [3]. It was shown that R5 treatment induced a profound analgesic effect that extended to at least one hour after the plasma level of the drug had completely disappeared due to rapid hydrolysis by tissue esterases. Because a related ketamine ester analogue with the same primary metabolite showed no such antinociceptive action, we are confident this analgesia is not mediated by an active metabolite
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