Dopamine neurons in the ventral periaqueductal gray modulate isoflurane anesthesia in rats

General anesthesia has been applied in surgery for more than 170 years, and there is little doubt that GABA_A receptors have an important role as anesthetic molecular targets, but its neural mechanisms remain unclear. Increasing researchers have shown that dopaminergic pathways in the brain are crucial for sleep and wake. General anesthesia-induced unconsciousness and natural sleep share some neural correlates. However, the role of GABA_A receptors in ventral periaqueductal gray (vPAG) dopamine (DA) neurons in the isoflurane-induced unconsciousness has yet to be identified.

In the present study, we used calcium fiber photometry recording to explore that the activity of ventral periaqueductal gray (vPAG) neurons. Then, rats were unilaterally microinjected with 6-hydroxydopamine into the vPAG area to determine the role of vPAG-DA neurons in isoflurane-induced-anesthesia. Furthermore, thirty SD rats were divided into three groups: a GABA_A R agonist-muscimol group, a GABA_A R antagonist-gabazine group, and a control group. Finally, whole-cell patch clamp was used to examine the effects of isoflurane and GABA_A receptor agonist/antagonist on vPAG-DA neurons.

The vPAG neurons were markedly inhibited during isoflurane anesthesia induction and that these neurons were activated during emergence from isoflurane anesthesia. Lesion to the vPAG-DA neurons shortened the induction time and prolonged the emergence time while increasing δ power in isoflurane anesthesia. Intracerebral injection of the GABA_A receptor agonist (muscimol) into the vPAG accelerated the induction of anesthesia and delayed recovery from isoflurane anesthesia, with a decrease of δ power and an augment of β power. Injection of GABA_A receptor antagonist gabazine generated the opposite effects. Isoflurane enhanced GABAergic transmission, and GABA_A receptor agonist partly increased isoflurane-induced inhibition of vPAG-DA neurons, while GABA_A receptor antagonist evidently attenuated GABAergic transmission.

Our results suggest that vPAG-DA neurons are involved in isoflurane anesthesia through activation of the GABA_A receptor.