Ever since its first use in surgery, general anesthesia has been regarded as a medical miracle enabling countless life-saving diagnostic and therapeutic interventions without pain sensation and traumatic memories. Despite several decades of research, there is a lack of understanding of how general anesthetics induce a reversible coma-like state. Emerging evidence suggests that even brief exposure to general anesthesia may have a lasting impact on mature and especially developing brains. Commonly used anesthetics have been shown to destabilize dendritic spines and induce an enhanced plasticity state, with effects on cognition, motor functions, mood, and social behavior. Herein, we review the effects of the most widely used general anesthetics on dendritic spine dynamics and discuss functional and molecular correlates with action mechanisms. We consider the impact of neurodevelopment, anatomical location of neurons, and their neurochemical profile on neuroplasticity induction, and review the putative signaling pathways. It emerges that in addition to possible adverse effects, the stimulation of synaptic remodeling with the formation of new connections by general anesthetics may present tremendous opportunities for translational research and neurorehabilitation.

Department of Psychiatry and Medical Psychology 3rd Faculty of Medicine of Charles University Prague Czech Republic

Experimental Neurobiology Program National Institute of Mental Health Topolová 748 250 67 Klecany Czech Republic

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Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011;115(6):1363–1381. doi: 10.1097/ALN.0b013e318238bba6. PubMed DOI PMC

Ali F, Gerhard DM, Sweasy K, Pothula S, Pittenger C, Duman RS, Kwan AC. Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines. Nat Commun. 2020;11(1):72. doi: 10.1038/s41467-019-13809-8. PubMed DOI PMC

Barber AF, Liang Q, Covarrubias M. Novel activation of voltage-gated K(+) channels by sevoflurane. J Biol Chem. 2012;287(48):40425–40432. doi: 10.1074/jbc.M112.405787. PubMed DOI PMC

Baumgart JP, Zhou ZY, Hara M, Cook DC, Hoppa MB, Ryan TA, Hemmings HC., Jr Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca2+ influx, not Ca2+-exocytosis coupling. Proc Natl Acad Sci USA. 2015;112(38):11959–11964. doi: 10.1073/pnas.1500525112. PubMed DOI PMC

Booth M. Opium: a history. 1st U.S. edn. New York: St. Martin's Press; 1998.

Borle RM. Textbook of oral and maxillofacial surgery. JP Medical Ltd.; 2014.

Briner A, De Roo M, Dayer A, Muller D, Habre W, Vutskits L. Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis. Anesthesiology. 2010;112(3):546–556. doi: 10.1097/ALN.0b013e3181cd7942. PubMed DOI

Briner A, Nikonenko I, De Roo M, Dayer A, Muller D, Vutskits L. Developmental stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology. 2011;115(2):282–293. doi: 10.1097/ALN.0b013e318221fbbd. PubMed DOI

Brosnan RJ, Thiesen R. Increased NMDA receptor inhibition at an increased Sevoflurane MAC. BMC Anesthesiol. 2012;12:9. doi: 10.1186/1471-2253-12-9. PubMed DOI PMC

Brown EN, Lydic R, Schiff ND. General anesthesia, sleep, and coma. N Engl J Med. 2010;363(27):2638–2650. doi: 10.1056/NEJMra0808281. PubMed DOI PMC

Brown EN, Purdon PL, Van Dort CJ. General anesthesia and altered states of arousal: a systems neuroscience analysis. Annu Rev Neurosci. 2011;34:601–628. doi: 10.1146/annurev-neuro-060909-153200. PubMed DOI PMC

Brown EN, Pavone KJ, Naranjo M. Multimodal general anesthesia: theory and practice. Anesth Analg. 2018;127(5):1246–1258. doi: 10.1213/ANE.0000000000003668. PubMed DOI PMC

Cao JL, Vialou VF, Lobo MK, Robison AJ, Neve RL, Cooper DC, Nestler EJ, Han MH. Essential role of the cAMP-cAMP response-element binding protein pathway in opiate-induced homeostatic adaptations of locus coeruleus neurons. Proc Natl Acad Sci USA. 2010;107(39):17011–17016. doi: 10.1073/pnas.1010077107. PubMed DOI PMC

Carter AJ. Dwale: an anaesthetic from old England. BMJ. 1999;319(7225):1623–1626. doi: 10.1136/bmj.319.7225.1623. PubMed DOI PMC

Cheng Y, He L, Prasad V, Wang S, Levy RJ. Anesthesia-induced neuronal apoptosis in the developing retina: a window of opportunity. Anesth Analg. 2015;121(5):1325–1335. doi: 10.1213/ANE.0000000000000714. PubMed DOI PMC

Ching S, Brown EN. Modeling the dynamical effects of anesthesia on brain circuits. Curr Opin Neurobiol. 2014;25:116–122. doi: 10.1016/j.conb.2013.12.011. PubMed DOI PMC

Correa AM. Gating kinetics of Shaker K+ channels are differentially modified by general anesthetics. Am J Physiol. 1998;275(4):C1009–1021. doi: 10.1152/ajpcell.1998.275.4.C1009. PubMed DOI

Crosby G, Culley DJ, Patel PM. At the sharp end of spines: anesthetic effects on synaptic remodeling in the developing brain. Anesthesiology. 2010;112(3):521–523. doi: 10.1097/ALN.0b013e3181cd795d. PubMed DOI PMC

Crowe SE, Ellis-Davies GC. Longitudinal in vivo two-photon fluorescence imaging. J Comp Neurol. 2014;522(8):1708–1727. doi: 10.1002/cne.23502. PubMed DOI PMC

De Roo M, Klauser P, Briner A, Nikonenko I, Mendez P, Dayer A, Kiss JZ, Muller D, Vutskits L. Anesthetics rapidly promote synaptogenesis during a critical period of brain development. PLoS ONE. 2009;4(9):e7043. doi: 10.1371/journal.pone.0007043. PubMed DOI PMC

Dong Y, Hong W, Tang Z, Gao Y, Wu X, Liu H. Sevoflurane leads to learning and memory dysfunction via breaking the balance of tPA/PAI-1. Neurochem Int. 2020;139:104789. doi: 10.1016/j.neuint.2020.104789. PubMed DOI

Eaton MM, Cao LQ, Chen Z, Franks NP, Evers AS, Akk G. Mutational analysis of the putative high-affinity propofol binding site in human beta3 homomeric GABAA receptors. Mol Pharmacol. 2015;88(4):736–745. doi: 10.1124/mol.115.100347. PubMed DOI PMC

Egan TD. Are opioids indispensable for general anaesthesia? Br J Anaesth. 2019;122(6):e127–e135. doi: 10.1016/j.bja.2019.02.018. PubMed DOI

Endo K, Yawo H. mu-Opioid receptor inhibits N-type Ca2+ channels in the calyx presynaptic terminal of the embryonic chick ciliary ganglion. J Physiol. 2000;524(Pt 3):769–781. doi: 10.1111/j.1469-7793.2000.00769.x. PubMed DOI PMC

Erturk A, Wang Y, Sheng M. Local pruning of dendrites and spines by caspase-3-dependent and proteasome-limited mechanisms. J Neurosci. 2014;34(5):1672–1688. doi: 10.1523/JNEUROSCI.3121-13.2014. PubMed DOI PMC

Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, Sprung J, Weaver AL, Schroeder DR, Warner DO. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128(5):e1053–1061. doi: 10.1542/peds.2011-0351. PubMed DOI PMC

Fodale V, Santamaria LB. Different actions of sevoflurane and propofol on central nicotinic receptors may explain differences in hypnotic antagonism by cholinesterase inhibitors. Br J Anaesth. 2004;92(5):773–774. doi: 10.1093/bja/aeh547. PubMed DOI

Franks NP. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci. 2008;9(5):370–386. doi: 10.1038/nrn2372. PubMed DOI

Franks NP, Zecharia AY. Sleep and general anesthesia. Can J Anaesth. 2011;58(2):139–148. doi: 10.1007/s12630-010-9420-3. PubMed DOI

Geoffroy H, Canestrelli C, Marie N, Noble F. Morphine-induced dendritic spine remodeling in rat nucleus accumbens is corticosterone dependent. Int J Neuropsychopharmacol. 2019;22(6):394–401. doi: 10.1093/ijnp/pyz014. PubMed DOI PMC

Gravenstein JS. Paracelsus and his contributions to anesthesia. Anesthesiology. 1965;26(6):805–811. doi: 10.1097/00000542-196511000-00016. PubMed DOI

Graziane NM, Sun S, Wright WJ, Jang D, Liu Z, Huang YH, Nestler EJ, Wang YT, Schluter OM, Dong Y. Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses. Nat Neurosci. 2016;19(7):915–925. doi: 10.1038/nn.4313. PubMed DOI PMC

Head BP, Patel HH, Niesman IR, Drummond JC, Roth DM, Patel PM. Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system. Anesthesiology. 2009;110(4):813–825. doi: 10.1097/ALN.0b013e31819b602b. PubMed DOI PMC

Hearing MC, Jedynak J, Ebner SR, Ingebretson A, Asp AJ, Fischer RA, Schmidt C, Larson EB, Thomas MJ. Reversal of morphine-induced cell-type-specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement. Proc Natl Acad Sci USA. 2016;113(3):757–762. doi: 10.1073/pnas.1519248113. PubMed DOI PMC

Hemmings HC, Jr, Yan W, Westphalen RI, Ryan TA. The general anesthetic isoflurane depresses synaptic vesicle exocytosis. Mol Pharmacol. 2005;67(5):1591–1599. doi: 10.1124/mol.104.003210. PubMed DOI

Herold K, Platholi J, Halpain S, Hemmings HC. Isoflurane induces dendritic spine loss in rat hippocampal neurons. New York: ABSTRACT Weill Cornell Medical College; 2013.

Hofacer RD, Deng M, Ward CG, Joseph B, Hughes EA, Jiang C, Danzer SC, Loepke AW. Cell age-specific vulnerability of neurons to anesthetic toxicity. Ann Neurol. 2013;73(6):695–704. doi: 10.1002/ana.23892. PubMed DOI PMC

Huang L, Yang G. Repeated exposure to ketamine-xylazine during early development impairs motor learning-dependent dendritic spine plasticity in adulthood. Anesthesiology. 2015;122(4):821–831. doi: 10.1097/ALN.0000000000000579. PubMed DOI PMC

Huang L, Cichon J, Ninan I, Yang G. Post-anesthesia AMPA receptor potentiation prevents anesthesia-induced learning and synaptic deficits. Sci Transl Med. 2016;8(344):344ra385. doi: 10.1126/scitranslmed.aaf7151. PubMed DOI PMC

Hung CF, Tsai CH, Su MJ. Opioid receptor independent effects of morphine on membrane currents in single cardiac myocytes. Br J Anaesth. 1998;81(6):925–931. doi: 10.1093/bja/81.6.925. PubMed DOI

Ibrahim AE, Ghoneim MM, Kharasch ED, Epstein RH, Groudine SB, Ebert TJ, Binstock WB, Philip BK, Sevoflurane Sedation Study G Speed of recovery and side-effect profile of sevoflurane sedation compared with midazolam. Anesthesiology. 2001;94(1):87–94. doi: 10.1097/00000542-200101000-00018. PubMed DOI

Ingram R, Kang H, Lightman S, Jane DE, Bortolotto ZA, Collingridge GL, Lodge D, Volianskis A. Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity. Neuropharmacology. 2018;142:30–40. doi: 10.1016/j.neuropharm.2018.06.008. PubMed DOI

Ito H, Watanabe Y, Isshiki A, Uchino H. Neuroprotective properties of propofol and midazolam, but not pentobarbital, on neuronal damage induced by forebrain ischemia, based on the GABAA receptors. Acta Anaesthesiol Scand. 1999;43(2):153–162. doi: 10.1034/j.1399-6576.1999.430206.x. PubMed DOI

Janssen PA, Niemegeers CJ, Schellekens KH, Verbruggen FJ, Van Nueten JM. The pharmacology of dehydrobenzperidol, a new potent and short acting neuroleptic agent chemically related to Haloperidol. Arzneimittelforschung. 1963;13:205–211. PubMed

Jeevakumar V, Kroener S. Ketamine administration during the second postnatal week alters synaptic properties of fast-spiking interneurons in the medial prefrontal cortex of adult mice. Cereb Cortex. 2016;26(3):1117–1129. doi: 10.1093/cercor/bhu293. PubMed DOI

Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23(3):876–882. doi: 10.1523/JNEUROSCI.23-03-00876.2003. PubMed DOI PMC

Jia M, Liu WX, Yang JJ, Xu N, Xie ZM, Ju LS, Ji MH, Martynyuk AE, Yang JJ. Role of histone acetylation in long-term neurobehavioral effects of neonatal exposure to sevoflurane in rats. Neurobiol Dis. 2016;91:209–220. doi: 10.1016/j.nbd.2016.03.017. PubMed DOI PMC

Jiang S, Hao Z, Li X, Bo L, Zhang R, Wang Y, Duan X, Kang R, Huang L. Ketamine destabilizes growth of dendritic spines in developing hippocampal neurons in vitro via a Rhodependent mechanism. Mol Med Rep. 2018;18(6):5037–5043. doi: 10.3892/mmr.2018.9531. PubMed DOI PMC

Jiang-Xie LF, Yin L, Zhao S, Prevosto V, Han BX, Dzirasa K, Wang F. A common neuroendocrine substrate for diverse general anesthetics and sleep. Neuron. 2019;102(5):1053–1065 e1054. doi: 10.1016/j.neuron.2019.03.033. PubMed DOI PMC

Jones MV, Brooks PA, Harrison NL. Enhancement of gamma-aminobutyric acid-activated Cl- currents in cultured rat hippocampal neurones by three volatile anaesthetics. J Physiol. 1992;449:279–293. doi: 10.1113/jphysiol.1992.sp019086. PubMed DOI PMC

Jones MV, Harrison NL, Pritchett DB, Hales TG. Modulation of the GABAA receptor by propofol is independent of the gamma subunit. J Pharmacol Exp Ther. 1995;274(2):962–968. PubMed

Kaech S, Brinkhaus H, Matus A. Volatile anesthetics block actin-based motility in dendritic spines. Proc Natl Acad Sci USA. 1999;96(18):10433–10437. doi: 10.1073/pnas.96.18.10433. PubMed DOI PMC

Kang E, Jiang D, Ryu YK, Lim S, Kwak M, Gray CD, Xu M, Choi JH, Junn S, Kim J, Xu J, Schaefer M, Johns RA, Song H, Ming GL, Mintz CD. Early postnatal exposure to isoflurane causes cognitive deficits and disrupts development of newborn hippocampal neurons via activation of the mTOR pathway. PLoS Biol. 2017;15(7):e2001246. doi: 10.1371/journal.pbio.2001246. PubMed DOI PMC

Klimscha W, Zimpfer M. The role of combined anesthesia: pros and cons anaesthesia, pain intensive care and emergency medicine. Milano: Springer; 1998.

Kodama M, Satoh Y, Otsubo Y, Araki Y, Yonamine R, Masui K, Kazama T. Neonatal desflurane exposure induces more robust neuroapoptosis than do isoflurane and sevoflurane and impairs working memory. Anesthesiology. 2011;115(5):979–991. doi: 10.1097/ALN.0b013e318234228b. PubMed DOI

Koo JW, Lobo MK, Chaudhury D, Labonte B, Friedman A, Heller E, Pena CJ, Han MH, Nestler EJ. Loss of BDNF signaling in D1R-expressing NAc neurons enhances morphine reward by reducing GABA inhibition. Neuropsychopharmacology. 2014;39(11):2646–2653. doi: 10.1038/npp.2014.118. PubMed DOI PMC

Krzisch M, Sultan S, Sandell J, Demeter K, Vutskits L, Toni N. Propofol anesthesia impairs the maturation and survival of adult-born hippocampal neurons. Anesthesiology. 2013;118(3):602–610. doi: 10.1097/ALN.0b013e3182815948. PubMed DOI

Landin JD, Palac M, Carter JM, Dzumaga Y, Santerre-Anderson JL, Fernandez GM, Savage LM, Varlinskaya EI, Spear LP, Moore SD, Swartzwelder HS, Fleming RL, Werner DF. General anesthetic exposure in adolescent rats causes persistent maladaptations in cognitive and affective behaviors and neuroplasticity. Neuropharmacology. 2019;150:153–163. doi: 10.1016/j.neuropharm.2019.03.022. PubMed DOI PMC

Leuner B, Shors TJ. New spines, new memories. Mol Neurobiol. 2004;29(2):117–130. doi: 10.1385/MN:29:2:117. PubMed DOI PMC

Li Y, Wang H, Niu L, Zhou Y. Chronic morphine exposure alters the dendritic morphology of pyramidal neurons in visual cortex of rats. Neurosci Lett. 2007;418(3):227–231. doi: 10.1016/j.neulet.2007.03.023. PubMed DOI

Li Y, Li X, Guo C, Li L, Wang Y, Zhang Y, Chen Y, Liu W, Gao L. Long-term neurocognitive dysfunction in offspring via NGF/ ERK/CREB signaling pathway caused by ketamine exposure during the second trimester of pregnancy in rats. Oncotarget. 2017;8(19):30956–30970. doi: 10.18632/oncotarget.16042. PubMed DOI PMC

Li Y, Li X, Zhao J, Li L, Wang Y, Zhang Y, Chen Y, Liu W, Gao L. Midazolam attenuates autophagy and apoptosis caused by ketamine by decreasing reactive oxygen species in the hippocampus of fetal rats. Neuroscience. 2018;388:460–471. doi: 10.1016/j.neuroscience.2018.03.040. PubMed DOI

Li Y, Xu J, Xu Y, Zhao XY, Liu Y, Wang J, Wang GM, Lv YT, Tang QY, Zhang Z. Regulatory effect of general anesthetics on activity of potassium channels. Neurosci Bull. 2018;34(5):887–900. doi: 10.1007/s12264-018-0239-1. PubMed DOI PMC

Liao D, Lin H, Law PY, Loh HH. Mu-opioid receptors modulate the stability of dendritic spines. Proc Natl Acad Sci USA. 2005;102(5):1725–1730. doi: 10.1073/pnas.0406797102. PubMed DOI PMC

Liao D, Grigoriants OO, Wang W, Wiens K, Loh HH, Law PY. Distinct effects of individual opioids on the morphology of spines depend upon the internalization of mu opioid receptors. Mol Cell Neurosci. 2007;35(3):456–469. doi: 10.1016/j.mcn.2007.04.007. PubMed DOI PMC

Lin D, Cao L, Wang Z, Li J, Washington JM, Zuo Z. Lidocaine attenuates cognitive impairment after isoflurane anesthesia in old rats. Behav Brain Res. 2012;228(2):319–327. doi: 10.1016/j.bbr.2011.12.010. PubMed DOI PMC

Lioudyno MI, Birch AM, Tanaka BS, Sokolov Y, Goldin AL, Chandy KG, Hall JE, Alkire MT. Shaker-related potassium channels in the central medial nucleus of the thalamus are important molecular targets for arousal suppression by volatile general anesthetics. J Neurosci. 2013;33(41):16310–16322. doi: 10.1523/JNEUROSCI.0344-13.2013. PubMed DOI PMC

Liu C, Au JD, Zou HL, Cotten JF, Yost CS. Potent activation of the human tandem pore domain K channel TRESK with clinical concentrations of volatile anesthetics. Anesth Analg. 2004;99(6):1715–1722. doi: 10.1213/01.ANE.0000136849.07384.44. PubMed DOI

Liu B, Ou G, Chen Y, Zhang J. Inhibition of protein tyrosine phosphatase 1B protects against sevoflurane-induced neurotoxicity mediated by ER stress in developing brain. Brain Res Bull. 2019;146:28–39. doi: 10.1016/j.brainresbull.2018.12.006. PubMed DOI

Lodge D, Anis NA. Effects of ketamine and three other anaesthetics on spinal reflexes and inhibitions in the cat. Br J Anaesth. 1984;56(10):1143–1151. doi: 10.1093/bja/56.10.1143. PubMed DOI

Long CW. An account of the first use of sulphuric ether by inhalation as an anaesthetic in surgical operations. Surv Anesthesiol. 1991;35(6):375. doi: 10.1097/00132586-199112000-00049. DOI

Lopes CM, Franks NP, Lieb WR. Actions of general anaesthetics and arachidonic pathway inhibitors on K+ currents activated by volatile anaesthetics and FMRFamide in molluscan neurones. Br J Pharmacol. 1998;125(2):309–318. doi: 10.1038/sj.bjp.0702069. PubMed DOI PMC

Martin JA, Werner CT, Mitra S, Zhong P, Wang ZJ, Gobira PH, Stewart AF, Zhang J, Erias K, Siemian JN, Hagarty D, Mueller LE, Neve RL, Li JX, Chandra R, Dietz KC, Lobo MK, Gancarz AM, Yan Z, Dietz DM. A novel role for the actin-binding protein drebrin in regulating opiate addiction. Nat Commun. 2019;10(1):4140. doi: 10.1038/s41467-019-12122-8. PubMed DOI PMC

Matsui A, Williams JT. Activation of micro-opioid receptors and block of Kir3 potassium channels and NMDA receptor conductance by L- and D-methadone in rat locus coeruleus. Br J Pharmacol. 2010;161(6):1403–1413. doi: 10.1111/j.1476-5381.2010.00967.x. PubMed DOI PMC

McFadzean I. The ionic mechanisms underlying opioid actions. Neuropeptides. 1988;11(4):173–180. doi: 10.1016/0143-4179(88)90072-8. PubMed DOI

Meng L, Qiu H, Wan L, Ai Y, Xue Z, Guo Q, Deshpande R, Zhang L, Meng J, Tong C, Liu H, Xiong L. Intubation and ventilation amid the COVID-19 outbreak: Wuhan's experience. Anesthesiology. 2020;132(6):1317–1332. doi: 10.1097/ALN.0000000000003296. PubMed DOI PMC

Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, Witztum J, Shaver DC, Rosenthal DL, Alway EJ, Lopez K, Meng Y, Nellissen L, Grosenick L, Milner TA, Deisseroth K, Bito H, Kasai H, Liston C. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019 doi: 10.1126/science.aat8078. PubMed DOI PMC

Murasaki O, Kaibara M, Nagase Y, Mitarai S, Doi Y, Sumikawa K, Taniyama K. Site of action of the general anesthetic propofol in muscarinic M1 receptor-mediated signal transduction. J Pharmacol Exp Ther. 2003;307(3):995–1000. doi: 10.1124/jpet.103.055772. PubMed DOI

Neuner J, Ovsepian SV, Dorostkar M, Filser S, Gupta A, Michalakis S, Biel M, Herms J. Pathological alpha-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb. Nat Commun. 2014;5:3915. doi: 10.1038/ncomms4915. PubMed DOI PMC

Nimchinsky EA, Sabatini BL, Svoboda K. Structure and function of dendritic spines. Annu Rev Physiol. 2002;64:313–353. doi: 10.1146/annurev.physiol.64.081501.160008. PubMed DOI

Ochs SM, Dorostkar MM, Aramuni G, Schon C, Filser S, Poschl J, Kremer A, Van Leuven F, Ovsepian SV, Herms J. Loss of neuronal GSK3beta reduces dendritic spine stability and attenuates excitatory synaptic transmission via beta-catenin. Mol Psychiatry. 2015;20(4):482–489. doi: 10.1038/mp.2014.55. PubMed DOI PMC

Ogden KK, Traynelis SF. New advances in NMDA receptor pharmacology. Trends Pharmacol Sci. 2011;32(12):726–733. doi: 10.1016/j.tips.2011.08.003. PubMed DOI PMC

Orser BA, Bertlik M, Wang LY, MacDonald JF. Inhibition by propofol (2,6 di-isopropylphenol) of the N-methyl-D-aspartate subtype of glutamate receptor in cultured hippocampal neurones. Br J Pharmacol. 1995;116(2):1761–1768. doi: 10.1111/j.1476-5381.1995.tb16660.x. PubMed DOI PMC

Ou M, Zhao W, Liu J, Liang P, Huang H, Yu H, Zhu T, Zhou C. The general anesthetic isoflurane bilaterally modulates neuronal excitability. iScience. 2020;23(1):100760. doi: 10.1016/j.isci.2019.100760. PubMed DOI PMC

Ovsepian SV, Olefir I, Westmeyer G, Razansky D, Ntziachristos V. Pushing the boundaries of neuroimaging with optoacoustics. Neuron. 2017;96(5):966–988. doi: 10.1016/j.neuron.2017.10.022. PubMed DOI

Ovsepian SV, O'Leary VB, Zaborszky L, Ntziachristos V, Dolly JO. Amyloid plaques of Alzheimer's disease as hotspots of glutamatergic activity. Neuroscientist. 2019;25(4):288–297. doi: 10.1177/1073858418791128. PubMed DOI PMC

Pal A, Das S. Chronic morphine exposure and its abstinence alters dendritic spine morphology and upregulates Shank1. Neurochem Int. 2013;62(7):956–964. doi: 10.1016/j.neuint.2013.03.011. PubMed DOI

Pancrazio JJ, Park WK, Lynch C., 3rd Inhalational anesthetic actions on voltage-gated ion currents of bovine adrenal chromaffin cells. Mol Pharmacol. 1993;43(5):783–794. PubMed

Papich MG. Saunders handbook of veterinary drugs: small and large animal. 4. St. Louis: Elsevier; 2016.

Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, Hanig JP, Patterson TA, Slikker W, Jr, Wang C. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011;33(2):220–230. doi: 10.1016/j.ntt.2011.01.001. PubMed DOI PMC

Pavel MA, Petersen EN, Wang H, Lerner RA, Hansen SB. Studies on the mechanism of general anesthesia. Proc Natl Acad Sci USA. 2020;117(24):13757–13766. doi: 10.1073/pnas.2004259117. PubMed DOI PMC

Perouansky M, Hemmings HC. Presynaptic actions of general anesthetics. Neural mechanisms of anesthesia. Contemporary clinical neuroscience. Totowa: Humana Press; 2003.

Persson J. Wherefore ketamine? Curr Opin Anaesthesiol. 2010;23(4):455–460. doi: 10.1097/ACO.0b013e32833b49b3. PubMed DOI

Phoumthipphavong V, Barthas F, Hassett S, Kwan AC. Longitudinal effects of ketamine on dendritic architecture in vivo in the mouse medial frontal cortex. Neuro. 2016 doi: 10.1523/ENEURO.0133-15.2016. PubMed DOI PMC

Platholi J, Herold KF, Hemmings HC, Jr, Halpain S. Isoflurane reversibly destabilizes hippocampal dendritic spines by an actin-dependent mechanism. PLoS ONE. 2014;9(7):e102978. doi: 10.1371/journal.pone.0102978. PubMed DOI PMC

Puskarjov M, Fiumelli H, Briner A, Bodogan T, Demeter K, Lacoh CM, Mavrovic M, Blaesse P, Kaila K, Vutskits L. K-Cl Cotransporter 2-mediated Cl- extrusion determines developmental stage-dependent impact of propofol anesthesia on dendritic spines. Anesthesiology. 2017;126(5):855–867. doi: 10.1097/ALN.0000000000001587. PubMed DOI

Qiu L, Zhu C, Bodogan T, Gomez-Galan M, Zhang Y, Zhou K, Li T, Xu G, Blomgren K, Eriksson LI, Vutskits L, Terrando N. Acute and long-term effects of brief sevoflurane anesthesia during the early postnatal period in rats. Toxicol Sci. 2016;149(1):121–133. doi: 10.1093/toxsci/kfv219. PubMed DOI

Qiu L, Pan W, Luo D, Zhang G, Zhou Z, Sun X, Yang JJ, M.H. J, Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice. J Neuroinflam. 2020 doi: 10.1186/s12974-019-1695-x. PubMed DOI PMC

Quinlan JJ, Homanics GE, Firestone LL. Anesthesia sensitivity in mice that lack the beta3 subunit of the gamma-aminobutyric acid type A receptor. Anesthesiology. 1998;88(3):775–780. doi: 10.1097/00000542-199803000-00030. PubMed DOI

RaiseAbdullahi P, Vafaei AA, Ghanbari A, Dadkhah M, Rashidy-Pour A. Time-dependent protective effects of morphine against behavioral and morphological deficits in an animal model of posttraumatic stress disorder. Behav Brain Res. 2019;364:19–28. doi: 10.1016/j.bbr.2019.01.058. PubMed DOI

Robinson DH, Toledo AH. Historical development of modern anesthesia. J Invest Surg. 2012;25(3):141–149. doi: 10.3109/08941939.2012.690328. PubMed DOI

Robinson TE, Gorny G, Savage VR, Kolb B. Widespread but regionally specific effects of experimenter- versus self-administered morphine on dendritic spines in the nucleus accumbens, hippocampus, and neocortex of adult rats. Synapse. 2002;46(4):271–279. doi: 10.1002/syn.10146. PubMed DOI

Rochefort NL, Konnerth A. Dendritic spines: from structure to in vivo function. EMBO Rep. 2012;13(8):699–708. doi: 10.1038/embor.2012.102. PubMed DOI PMC

Sassano-Higgins S, Baron D, Juarez G, Esmaili N, Gold M. A review of ketamine abuse and diversion. Depress Anxiety. 2016;33(8):718–727. doi: 10.1002/da.22536. PubMed DOI

Satomoto M, Satoh Y, Terui K, Miyao H, Takishima K, Ito M, Imaki J. Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology. 2009;110(3):628–637. doi: 10.1097/ALN.0b013e3181974fa2. PubMed DOI

Scallet AC, Schmued LC, Slikker W, Jr, Grunberg N, Faustino PJ, Davis H, Lester D, Pine PS, Sistare F, Hanig JP. Developmental neurotoxicity of ketamine: morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons. Toxicol Sci. 2004;81(2):364–370. doi: 10.1093/toxsci/kfh224. PubMed DOI

Schaefer ML, Wang M, Perez PJ, Coca Peralta W, Xu J, Johns RA. Nitric oxide donor prevents neonatal isoflurane-induced impairments in synaptic plasticity and memory. Anesthesiology. 2019;130(2):247–262. doi: 10.1097/ALN.0000000000002529. PubMed DOI PMC

Schwieler L, Delbro DS, Engberg G, Erhardt S. The anaesthetic agent propofol interacts with GABA(B)-receptors: an electrophysiological study in rat. Life Sci. 2003;72(24):2793–2801. doi: 10.1016/s0024-3205(03)00182-6. PubMed DOI

Sergeeva OA, Andreeva N, Garret M, Scherer A, Haas HL. Pharmacological properties of GABAA receptors in rat hypothalamic neurons expressing the epsilon-subunit. J Neurosci. 2005;25(1):88–95. doi: 10.1523/JNEUROSCI.3209-04.2005. PubMed DOI PMC

Sesena E, Vega R, Soto E. Activation of mu-opioid receptors inhibits calcium-currents in the vestibular afferent neurons of the rat through a cAMP dependent mechanism. Front Cell Neurosci. 2014;8:90. doi: 10.3389/fncel.2014.00090. PubMed DOI PMC

Sleigh J, Harvey M, Voss L, Denny B. Ketamine—more mechanisms of action than just NMDA blockade. Trends Anaesth Crit Care. 2014;4(2–3):76–81. doi: 10.1016/j.tacc.2014.03.002. DOI

Snyder SH, Pasternak GW. Historical review: opioid receptors. Trends Pharmacol Sci. 2003;24(4):198–205. doi: 10.1016/S0165-6147(03)00066-X. PubMed DOI

Spiga S, Puddu MC, Pisano M, Diana M. Morphine withdrawal-induced morphological changes in the nucleus accumbens. Eur J Neurosci. 2005;22(9):2332–2340. doi: 10.1111/j.1460-9568.2005.04416.x. PubMed DOI

Stock L, Hosoume J, Cirqueira L, Treptow W. Binding of the general anesthetic sevoflurane to ion channels. PLoS Comput Biol. 2018;14(11):e1006605. doi: 10.1371/journal.pcbi.1006605. PubMed DOI PMC

Stratmann G, May LD, Sall JW, Alvi RS, Bell JS, Ormerod BK, Rau V, Hilton JF, Dai R, Lee MT, Visrodia KH, Ku B, Zusmer EJ, Guggenheim J, Firouzian A. Effect of hypercarbia and isoflurane on brain cell death and neurocognitive dysfunction in 7-day-old rats. Anesthesiology. 2009;110(4):849–861. doi: 10.1097/ALN.0b013e31819c7140. PubMed DOI

Sun L. Early childhood general anaesthesia exposure and neurocognitive development. Br J Anaesth. 2010;105(Suppl 1):i61–68. doi: 10.1093/bja/aeq302. PubMed DOI PMC

Tan H, Ren RR, Xiong ZQ, Wang YW. Effects of ketamine and midazolam on morphology of dendritic spines in hippocampal CA1 region of neonatal mice. Chin Med J (engl) 2009;122(4):455–459. PubMed

Tang X, Li Y, Ao J, Ding L, Liu Y, Yuan Y, Wang Z, Wang G. Role of alpha7nAChR-NMDAR in sevoflurane-induced memory deficits in the developing rat hippocampus. PLoS ONE. 2018;13(2):e0192498. doi: 10.1371/journal.pone.0192498. PubMed DOI PMC

TerRiet MF, DeSouza GJ, Jacobs JS, Young D, Lewis MC, Herrington C, Gold MI. Which is most pungent: isoflurane, sevoflurane or desflurane? Br J Anaesth. 2000;85(2):305–307. doi: 10.1093/bja/85.2.305. PubMed DOI

Torturo CL, Zhou ZY, Ryan TA, Hemmings HC. Isoflurane inhibits dopaminergic synaptic vesicle exocytosis coupled to CaV2.1 and CaV2.2 in rat midbrain neurons. eNeuro. 2019;6:1. doi: 10.1523/ENEURO.0278-18.2018. PubMed DOI PMC

Trachtenberg JT, Chen BE, Knott GW, Feng G, Sanes JR, Welker E, Svoboda K. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature. 2002;420(6917):788–794. doi: 10.1038/nature01273. PubMed DOI

Trapani G, Altomare C, Liso G, Sanna E, Biggio G. Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery. Curr Med Chem. 2000;7(2):249–271. doi: 10.2174/0929867003375335. PubMed DOI

van Rijn RM, Whistler JL, Waldhoer M. Opioid-receptor-heteromer-specific trafficking and pharmacology. Curr Opin Pharmacol. 2010;10(1):73–79. doi: 10.1016/j.coph.2009.09.007. PubMed DOI PMC

Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem. 2004;73:953–990. doi: 10.1146/annurev.biochem.73.011303.073940. PubMed DOI

Wei H, Liang G, Yang H, Wang Q, Hawkins B, Madesh M, Wang S, Eckenhoff RG. The common inhalational anesthetic isoflurane induces apoptosis via activation of inositol 1,4,5-trisphosphate receptors. Anesthesiology. 2008;108(2):251–260. doi: 10.1097/01.anes.0000299435.59242.0e. PubMed DOI

Wenzel M, Leunig A, Han S, Peterka DS, Yuste R. Prolonged anesthesia alters brain synaptic architecture. Proc Natl Acad Sci USA. 2021 doi: 10.1073/pnas.2023676118. PubMed DOI PMC

Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110(4):796–804. doi: 10.1097/01.anes.0000344728.34332.5d. PubMed DOI PMC

Wu Z, Li X, Zhang Y, Tong D, Wang L, Zhao P. Effects of sevoflurane exposure during mid-pregnancy on learning and memory in offspring rats: beneficial effects of maternal exercise. Front Cell Neurosci. 2018;12:122. doi: 10.3389/fncel.2018.00122. PubMed DOI PMC

Wu L, Zhao H, Weng H, Ma D. Lasting effects of general anesthetics on the brain in the young and elderly: "mixed picture" of neurotoxicity, neuroprotection and cognitive impairment. J Anesth. 2019;33(2):321–335. doi: 10.1007/s00540-019-02623-7. PubMed DOI PMC

Xiao H, Liu B, Chen Y, Zhang J. Learning, memory and synaptic plasticity in hippocampus in rats exposed to sevoflurane. Int J Dev Neurosci. 2016;48:38–49. doi: 10.1016/j.ijdevneu.2015.11.001. PubMed DOI

Yang G, Chang PC, Bekker A, Blanck TJ, Gan WB. Transient effects of anesthetics on dendritic spines and filopodia in the living mouse cortex. Anesthesiology. 2011;115(4):718–726. doi: 10.1097/ALN.0b013e318229a660. PubMed DOI PMC

Yip GM, Chen ZW, Edge CJ, Smith EH, Dickinson R, Hohenester E, Townsend RR, Fuchs K, Sieghart W, Evers AS, Franks NP. A propofol binding site on mammalian GABAA receptors identified by photolabeling. Nat Chem Biol. 2013;9(11):715–720. doi: 10.1038/nchembio.1340. PubMed DOI PMC

Yu D, Jiang Y, Gao J, Liu B, Chen P. Repeated exposure to propofol potentiates neuroapoptosis and long-term behavioral deficits in neonatal rats. Neurosci Lett. 2013;534:41–46. doi: 10.1016/j.neulet.2012.12.033. PubMed DOI

Yuste R. Dendritic spines. Cambridge: MIT Press; 2010.

Zhang L, Oz M, Stewart RR, Peoples RW, Weight FF. Volatile general anaesthetic actions on recombinant nACh alpha 7, 5-HT3 and chimeric nACh alpha 7–5-HT3 receptors expressed in Xenopus oocytes. Br J Pharmacol. 1997;120(3):353–355. doi: 10.1038/sj.bjp.0700934. PubMed DOI PMC

Zhang Y, Dong Y, Wu X, Lu Y, Xu Z, Knapp A, Yue Y, Xu T, Xie Z. The mitochondrial pathway of anesthetic isoflurane-induced apoptosis. J Biol Chem. 2010;285(6):4025–4037. doi: 10.1074/jbc.M109.065664. PubMed DOI PMC

Zhang S, Liang Z, Sun W, Pei L (2017) Repeated propofol anesthesia induced downregulation of hippocampal miR-132 and learning and memory impairment of rats. Brain Res Sep 1 1670:156-164. 10.1016/j.brainres.2017.04.011 PMID:28465226 PubMed

Zhang X, Zhao J, Chang T, Wang Q, Liu W, Gao L. Ketamine exerts neurotoxic effects on the offspring of pregnant rats via the Wnt/beta-catenin pathway. Environ Sci Pollut Res Int. 2020;27(1):305–314. doi: 10.1007/s11356-019-06753-z. PubMed DOI

Zhang Z, Zhang J, Li J, Zhang J, Chen L, Li Y, Guo G. Ketamine regulates phosphorylation of CRMP2 to mediate dendritic spine plasticity. J Mol Neurosci. 2020;70(3):353–364. doi: 10.1007/s12031-019-01419-4. PubMed DOI

Zhao LL, Liu H, Zhang YY, Wei JQ, Han Y, Han L, Yang JP. A Comparative study on efficacy and safety of propofol versus dexmedetomidine in sleep apnea patients undergoing drug-induced sleep endoscopy: a CONSORT-prospective, Randomized controlled clinical trial. Biomed Res Int. 2018;2018:8696510. doi: 10.1155/2018/8696510. PubMed DOI PMC

Zhou C, Liu J, Chen XD. General anesthesia mediated by effects on ion channels. World J Crit Care Med. 2012;1(3):80–93. doi: 10.5492/wjccm.v1.i3.80. PubMed DOI PMC

Zhou B, Chen L, Liao P, Huang L, Chen Z, Liao D, Yang L, Wang J, Yu G, Wang L, Zhang J, Zuo Y, Liu J, Jiang R. Astroglial dysfunctions drive aberrant synaptogenesis and social behavioral deficits in mice with neonatal exposure to lengthy general anesthesia. PLoS Biol. 2019;17(8):e3000086. doi: 10.1371/journal.pbio.3000086. PubMed DOI PMC

Zimering JH, Dong Y, Fang F, Huang L, Zhang Y, Xie Z. Anesthetic sevoflurane causes rho-dependent filopodial shortening in mouse neurons. PLoS ONE. 2016;11(7):e0159637. doi: 10.1371/journal.pone.0159637. PubMed DOI PMC