Designer Receptors Exclusively Activated by Designer Drugs were used to excite calcium/calmodulin–dependent protein kinase 2α–positive neurons in the parabrachial nucleus region of adult male rats without anesthesia (nine rats), with dexmedetomidine (low dose: 0.3 µg · kg−1 · min−1 for 45 min, eight rats; high dose: 4.5 µg · kg−1 · min−1 for 10 min, seven rats), or with ketamine (low dose: 2 mg · kg−1 · min−1 for 30 min, seven rats; high dose: 4 mg · kg−1 · min−1 for 15 min, eight rats). For control experiments (same rats and treatments), the Designer Receptors Exclusively Activated by Designer Drugs were not excited. The electroencephalogram and anesthesia recovery times were recorded and analyzed.
Parabrachial nucleus excitation reduced delta power in the prefrontal electroencephalogram with low-dose dexmedetomidine for the 150-min analyzed period, excepting two brief periods (peak median bootstrapped difference [clozapine-N-oxide – saline] during dexmedetomidine infusion = −6.06 [99% CI = −12.36 to −1.48] dB, P = 0.007). However, parabrachial nucleus excitation was less effective at reducing delta power with high-dose dexmedetomidine and low- and high-dose ketamine (peak median bootstrapped differences during high-dose [dexmedetomidine, ketamine] infusions = [−1.93, −0.87] dB, 99% CI = [−4.16 to −0.56, −1.62 to −0.18] dB, P = [0.006, 0.019]; low-dose ketamine had no statistically significant decreases during the infusion). Recovery time differences with parabrachial nucleus excitation were not statistically significant for dexmedetomidine (median difference for [low, high] dose = [1.63, 11.01] min, 95% CI = [−20.06 to 14.14, −20.84 to 23.67] min, P = [0.945, 0.297]) nor low-dose ketamine (median difference = 12.82 [95% CI: −3.20 to 39.58] min, P = 0.109) but were significantly longer for high-dose ketamine (median difference = 11.38 [95% CI: 1.81 to 24.67] min, P = 0.016).
These results suggest that the effectiveness of parabrachial nucleus excitation to change the neurophysiologic and behavioral effects of anesthesia depends on the anesthetic’s molecular target.
- The parabrachial nucleus is an arousal area in the brainstem primarily composed of excitatory glutamatergic neurons
- Stimulation of the parabrachial nucleus reduces cortical delta oscillation power and promotes arousal during or after administration of anesthetics targeting principally the γ-aminobutyric acid type A receptor
- The effects of parabrachial nucleus stimulation on anesthetics with other molecular targets, such as dexmedetomidine or ketamine, are incompletely understood
- Chemogenetic excitation of parabrachial excitatory neurons in adult male rats reduced cortical delta power during low-dose dexmedetomidine but not during high-dose dexmedetomidine or ketamine anesthesia
- Changes in cortical delta power did not correspond to changes in time to recovery from anesthesia
- These observations suggest that the effectiveness of parabrachial nucleus excitation to change the neurophysiologic and behavioral effects of anesthesia depends on the molecular mechanisms of actions of general anesthetics