Basic metabolic and vascular effects of ketamine and its interaction with fentanyl

Abstract

Ketamine is a short-acting general anesthetic with hallucinogenic, analgesic, and amnestic properties. In addition to its anesthetic use, ketamine is commonly abused in rave settings. While safe when used by medical professionals, uncontrolled recreational use of ketamine is dangerous, especially when mixed with other sedative drugs, including alcohol, benzodiazepines, and opioid drugs. Since synergistic antinociceptive interactions between opioids and ketamine were demonstrated in both preclinical and clinical studies, such an interaction could exist for the hypoxic effects of opioid drugs. Here, we focused on the basic physiological effects of ketamine as a recreational drug and its possible interactions with fentanyl-a highly potent opioid that induces strong respiratory depression and robust brain hypoxia. By using multi-site thermorecording in freely-moving rats, we showed that intravenous ketamine at a range of human relevant doses (3, 9, 27 mg/kg) dose-dependently increases locomotor activity and brain temperature, as assessed in the nucleus accumbens (NAc). By determining temperature differentials between the brain, temporal muscle, and skin, we showed that the brain hyperthermic effect of ketamine results from increased intracerebral heat production, an index of metabolic neural activation, and decreased heat loss due to peripheral vasoconstriction. By using oxygen sensors coupled with high-speed amperometry we showed that ketamine at the same doses increases NAc oxygen levels. Finally, co-administration of ketamine with intravenous fentanyl results in modest enhancement of fentanyl-induced brain hypoxia also enhancing the post-hypoxic oxygen increase. Therefore, in contrast to fentanyl, ketamine increases brain oxygenation but potentiates brain hypoxia induced by fentanyl.

Keywords: Brain hypoxia; Brain oxygen; Brain temperature; Hyperoxia; Metabolic brain activation; Oxygen sensors; Peripheral vasoconstriction; Respiratory depression.

Figure 1.

Mean (±SEM) changes in temperature in the NAc, temporal muscle and subcutaneous space induced by iv injections of ketamine at 3, 9 and 27 mg/kg in freely moving rats. A = changes in absolute temperatures, B = changes relative to baseline (=0°C), C = changes in brain-muscle and skin-muscle differentials; D = changes in locomotor activity. Filled symbols show values significantly different from pre-injection baseline. n is the number of averaged tests.

Figure 2.

Mean (±SEM) changes in NAc oxygen levels induced by iv injections of ketamine at 3, 9 and 27 mg/kg in freely moving rats. A = slow changes assessed with 1-min time resolution; B = phasic changes assessed with 10-a time resolution. Filled symbols show values significantly different from pre-injection baseline. n is the number of averaged tests.

Figure 3.

Time-dependent relationships between changes in NAc oxygen levels and changes in NAc-muscle (A and C) and skin-muscle differentials (B and D) following iv injection of ketamine (9 mg/kg) and 1-min tail-pinch. After ketamine injection, oxygen levels in the NAc rapidly increased while both temperature differentials remained unchanged (A and B). Then changes in NAc levels were tightly correlated with changes in both differentials, showing strong linear correlation with brain-muscle differentials, an index of intra-brain heat production and skin-muscle differentials. While similar correlations were evident for changes in NAc levels and both differentials (C and D), the delay in changes of both differentials was absent. 1, 2, 3 show values for the first, second, and third minutes after the start of ketamine injection and start of 1-min tail-pinch.

Figure 4.

Mean (±SEM) changes in NAc oxygen levels induced by iv injections of fentanyl (20 μg/kg) and its mixture with ketamine (9 mg/kg). A = slow changes assessed with 1-min time resolution; B = phasic changes assessed with 10-a time resolution. Filled symbols show values significantly different from pre-injection baseline. Black solid line with asterisk mark shows significant between-group differences in NAc oxygen levels. n is the number of averaged tests. Green curve shows oxygen changes induced by ketamine alone (repeated from Figure 2.