The discovery and refinement of general anesthesia (GA) makes surgery and other invasive medical procedures more humane, predominantly through the induction of loss of consciousness and analgesia, or the loss of pain perception. However, it is not uncommon for patients to regain consciousness under GA and still experience pain relief. It is believed that low-dose general anesthesia drugs may induce analgesia through acting on supraspinal centers in the brain, such as the amygdala, to dissociate pain from the perception of noxious stimuli [1].   

A nociceptive stimulus, such as a physical injury, activates free nerve endings of C-fibers and A-delta fibers, which form excitatory synapses with projection neurons in the dorsal horn of the spinal cord. These projection neuron axons then ascend via the anterolateral fasciculus, a pathway of axon fibers traveling along the spinal cord to reach the brain. These axons synapse in the periaqueductal gray, the thalamus, the amygdala, and primary/secondary somatosenstory cortices [2]. Typically, it is within these regions that complex molecular cascades ultimately evoke the perception of pain.    

In vivo calcium imaging revealed strong c-Fos presence in a cluster of cells in the central amygdala (CeA) after exposure to general anesthesia, but not oxygen. Since its discovery in 1982, c-Fos has been used as a reliable marker of neural activity; this research suggests that the amygdala was activated during anesthesia above the expected level. Further investigation showed these CeA cells were all GABAergic, or inhibitory. Given the nociceptive pathway discussed in the above paragraph, these GABAergic CeA cells are in a prime position to suppress the activity of pain-activated neurons involved in the perception of pain [1]. Note that the perception of pain is distinct from the sensation of pain itself. 

In a murine model treated with GA, researchers demonstrated that optogenetic activation of this cluster of CeA cells decreased reflexive and recuperative responses to acute, persistent pain. On the other hand, the inhibition of this ensemble led to an exacerbated increase in coping behaviors, such as paw licking or face wiping [3]. These data suggest that the central amygdala region is related to the pain-relieving effects of anesthesia. Importantly, activation of this cluster had no effect on general motor or motivational behaviors, nor on the power spectrum of an EEG, indicating these neurons do not alter consciousness, and are rather specific to pain perception.  

Somatostatin, also known as growth hormone-inhibiting hormone, is a regulatory peptide which acts as an endogenous inhibitory regulator of the secretory and proliferative properties of target cells [4]. Recent evidence shows somatostatin-expressing cells in the CeA can induce pain relief. These somatostatin neurons mediate fear and threat responses, which could relate to the phenomenon of stress-induced analgesia (SIA) [3]. However, the cluster of CeA neuronal cells activated by GA was shown to be suppressed by stress, suggesting the CeA cells in GA are not involved in SIA [1]. Therefore, SIA may be a distinct type of analgesia, although it also involves clusters of neuronal cells in the CeA. Critically, these studies in the amygdala show analgesia with anesthesia is not entirely caused by suppression of pain sensation. Rather, anesthetics, through GABAergic mechanisms, also interact with the pre-existing, intricate circuitry involved in the endogenous control of pain perception.  

In 0.1-0.2% of surgeries using GA, the suppression of consciousness is not always complete and can lead to traumatic memories for the patient, suggesting some nociceptive properties are still active and can engage memory circuits in these cases. It is speculated that the CeA ensemble activated by GA is not sufficiently engaged in these cases, permitting the formation of traumatic pain memories [1,5].  

Through an enhanced research effort, a full picture of this particular CeA ensemble’s properties may be gleaned. This has the potential to lead to more effective therapeutic endeavors, including the production of better anesthetics and even chronic pain relief therapies. It could also give us greater insight into the true nature of memory and consciousness, two fundamental aspects of the human experience.  

References  

1. Hua, T., Chen, B., Lu, D., Sakurai, K., Zhao, S., Han, B.-X., Kim, J., Yin, L., Chen, Y., Lu, J., & Wang, F. (2020). General anesthetics activate a potent central pain-suppression circuit in the amygdala. Nature Neuroscience, 23(7), 854–868. https://doi.org/10.1038/s41593-020-0632-8 

2. Brown, E. N., Purdon, P. L., & Van Dort, C. J. (2011). General anesthesia and altered states of arousal: A systems neuroscience analysis. Annual Review of Neuroscience, 34(1), 601–628. https://doi.org/10.1146/annurev-neuro-060909-153200  

3. McCall, N. M., Wojick, J. A., & Corder, G. (2020). Anesthesia analgesia in the amygdala. Nature Neuroscience, 23(7), 783–785. https://doi.org/10.1038/s41593-020-0645-3  

4. Patel, Y. C. (1999). Somatostatin and its receptor family. Frontiers in Neuroendocrinology, 20(3), 157–198. https://doi.org/10.1006/frne.1999.0183  

5. Samuel, N., Taub, A. H., Paz, R., & Raz, A. (2018). Implicit aversive memory under anaesthesia in animal models: A narrative review. British Journal of Anaesthesia, 121(1), 219–232. https://doi.org/10.1016/j.bja.2018.05.046  

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