Background & Aims

Nitrous oxide is an anesthetic gas that, at subanesthetic concentrations, has potent analgesic effects. Despite its widespread clinical use, analgesic mechanisms in the brain remain insufficiently studied. We have recently shown that subanesthetic nitrous oxide induced changes in functional brain connectivity and spatiotemporal dynamics [1, 2]; the objective of this study was to investigate network-level mechanisms of analgesia in humans exposed to subanesthetic nitrous oxide. Because brain networks that include the insula and somatosensory cortices are associated with changes in pain perception and analgesia [3-7], our investigation focused on examining the effects of pain and nitrous oxide on whole-brain functional connectivity with the insula and somatosensory cortex.

Methods

Healthy volunteers (N = 21, Female, N=10; Age = 25.55 ± 4.01 yr.) consented to a clinical trial (NCT03435055) to assess the effect of subanesthetic nitrous oxide (35% Nitrous). fMRI data was acquired before and during exposure to nitrous, at rest (REST) and with a tonic cuff stimulus (CUFF). Cuff pressure calibrated for each volunteer to evoke moderate pain (40/100) was applied to the leg for 6-minutes. After the stimulus, volunteers reported perceived intensity and unpleasantness on a (0-10) scale from 0 = ‘no pain’, to 10 = ‘worst pain imaginable’. Paired t-test determined differences in pain ratings before and during nitrous. Condition-specific beta maps measursed whole brain functional connectivity from the right somatosensory cortex (S1-leg) and insula subregions using the CONN toolbox [4, 8, 9]. Flexible factorial in SPM12 assessed the effects of CUFF and Nitrous. Significance determined by FDR cluster level-corrected p < 0.05 derived from a voxel-wise uncorrected p < 0.001.

Results

Participants reported lower cuff pain intensity and unpleasantness ratings during exposure to nitrous oxide compared to before nitrous (intensity, p = 0.0004, unpleasantness, p = 0.0002). Prior to exposure to nitrous, functional connectivity between the left anterior insula and S1 was significantly higher (p = 0.006) during CUFF compared to REST. Connectivity between S1-leg and the angular gyrus (p < 0.001), precuneus (p = 0.004), and orbitofrontal cortex (p = 0.010), regions associated with the default mode network, decreased during CUFF compared to REST. During CUFF and exposure to nitrous oxide connectivity between the left anterior insula and the superior frontal gyrus (p = 0.001) and medial frontal gyrus (p = 0.001) was lower compared to CUFF before nitrous oxide. Notably, during both CUFF and Nitrous, S1-leg functional connectivity to superior temporal gyrus (p = 0.004), insula (p = 0.033) and cingulate (p = 0.033) was also significantly lower compared to CUFF prior to nitrous.

Conclusions

Subanesthetic nitrous oxide significantly reduced subjective tonic cuff pain intensity and unpleasantness. Moreover, functional connectivity between the insula and S1-leg increased with the tonic cuff stimulus and significantly decreased during nitrous oxide administration.
These findings suggest one of the analgesic mechanisms of nitrous oxide includes the disruption of functional connectivity between the insula and S1-leg.

References

1.Dai, R., et al., Psychedelic concentrations of nitrous oxide reduce functional differentiation in frontoparietal and somatomotor cortical networks. Commun Biol, 2023. 6(1): p. 1284.
2.Dai, R., et al., Classical and non-classical psychedelic drugs induce common network changes in human cortex. Neuroimage, 2023. 273: p. 120097.
3.Harris, R.E., et al., Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. Anesthesiology, 2013. 119(6): p. 1453-64.
4.Kim, J., et al., Sustained deep-tissue pain alters functional brain connectivity. Pain, 2013. 154(8): p. 1343-51.
5.Ichesco, E., et al., Altered resting state connectivity of the insular cortex in individuals with fibromyalgia. J Pain, 2014. 15(8): p. 815-826.e1.
6.Harte, S.E., et al., Pharmacologic attenuation of cross-modal sensory augmentation within the chronic pain insula. Pain, 2016. 157(9): p. 1933-45.
7.Mawla, I., et al., Greater Somatosensory Afference With Acupuncture Increases Primary Somatosensory Connectivity and Alleviates Fibromyalgia Pain via Insular ?-Aminobutyric Acid: A Randomized Neuroimaging Trial. Arthritis Rheumatol, 2021. 73(7): p. 1318-1328.
8.Ichesco, E., et al., Altered resting state connectivity of the insular cortex in individuals with fibromyalgia. J Pain, 2014. 15(8): p. 815-826 e1.
9.Whitfield-Gabrieli, S. and A. Nieto-Castanon, Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect, 2012. 2(3): p. 125-41.

Presenting Author

Tony E. Larkin

Poster Authors

Tony Larkin

PhD

University of Michigan

Lead Author

E-mail

Zirui Huang

University of Michigan

Lead Author

E-mail

Rui Dai

University of Michigan

Lead Author

E-mail

Ishtiaq Mawla

PhD

University of Michigan

Lead Author

E-mail

Vijay Tarnal

M.D.

University of Michigan

Lead Author

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Phillip Vlisides

M.D.

University of Michigan

Lead Author

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Ellen Janke

M.D.

University of Michigan

Lead Author

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Amy McKinney

M.A.

University of Michigan

Lead Author

E-mail

Chelsea Kaplan

University Of Michigan

Lead Author

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Steven Harte

University of Michigan

Lead Author

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Daniel Clauw

M.D.

University of Michigan

Lead Author

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Paul Picton

MD

University of Michigan

Lead Author

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George Mashour

M.D.

University of Michigan

Lead Author

E-mail

Richard Harris

Ph.D

University of California-Irvine

Lead Author

E-mail

Eric Ichesco

University of Michigan

Lead Author

E-mail

Topics

  • Pain Imaging