The serotonin 2C receptor agonist WAY-163909 attenuates ketamine-induced hypothermia in mice

Anesthesia-Induced Hypothermia (AIH) has been reported to be the cause of many postoperative adverse effects, including increased mortality, decreased immune responses, cardiac events, and a greater prevalence of postoperative surgical wound infections. AIH can in some cases be minimized with pre-warming fluids and gases and forced-air heating systems, but such techniques are not always effective and can result in patient burns or other adverse effects. Stimulation of 5-HT₂ receptors has been reported to increase body temperature through a variety of mechanisms, and as such, may be a viable target for pharmacologically minimizing AIH. In the present study, we examined the effects of 5-HT₂ receptor stimulation on hypothermia induced by the injectable anesthetic ketamine in Swiss-Webster mice using rectal thermometry. We report that ketamine dose-dependently induced hypothermia, and mice did not become tolerant to this effect of ketamine over the course of three injections spaced at once per week. Ketamine-induced hypothermia was significantly attenuated by pretreatment with the selective 5-HT_2C receptor agonist WAY-163909 but not by pretreatment with the mixed 5-HT_2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Moreover, the blockade of ketamine-induced hypothermia by WAY-163909 was reversed by pretreatment with the selective 5-HT_2C receptor antagonist SB-242084. These findings demonstrate that stimulation of 5-HT_2C receptors can reduce AIH, at least for ketamine-induced hypothermia. They warrant further study of the pharmacological and neurobiological mechanisms underlying this interaction and its extension to other anesthetics. Furthermore, these findings suggest that the maintenance of body temperature during surgery may be a new clinical use for 5-HT_2C receptor agonists.