, Volume 232, Issue 24, pp 4433–4444 | Cite as

Differential effects of general anesthetics on anxiety-like behavior in formalin-induced pain: involvement of ERK activation in the anterior cingulate cortex

  • Cong Luo
  • Yan-Ling Zhang
  • Wei Luo
  • Fiona H Zhou
  • Chang-Qi Li
  • Jun-Mei XuEmail author
  • Ru-Ping DaiEmail author
Original Investigation



Pain-related anxiety and depression are well known to be comorbid with chronic pain and adversely affect patient quality of life. Recent studies have shown that anxiety-like behaviors also develop with acute surgical pain, but the effects of general anesthetics on acute pain-related anxiety are unknown.


The present study aimed to compare the effects of different general anesthetics on anxiety-like behaviors that follow formalin-induced acute pain in a rat model.


Formalin-induced acute inflammatory pain was established by intraplantar injection of 1 % formalin without anesthesia or with anesthesia using the clinical anesthetics sevoflurane, propofol, or pentobarbital sodium. Anxiety-like behaviors were studied using the open-field test and elevated plus maze. Phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2 expression in the anterior cingulate cortex (ACC) and spinal cord was examined using immunohistochemistry.


Anxiety-like behaviors were observed at 24 and 72 h post-formalin injection. Concomitantly, p-ERK 1/2 expression was upregulated in the ACC at 1 and 24 h post-formalin injection. While all three general anesthetics effectively blocked nociceptive responses and activation of ERK in the rat ACC following formalin injection during anesthesia, only sevoflurane inhibited ERK activation in the spinal cord and ACC at 24 h post-injection.


This study suggests that sevoflurane, but not intravenous anesthetics, inhibits pain-related anxiety, along with ERK activation in the ACC, probably through inhibition of spinal nociceptive transmission. Intraoperative application of inhaled anesthetics may be a better choice to reduce postoperative anxiety.


Anxiety Anesthetics Sevoflurane Propofol Extracellular signal-regulated kinase Anterior cingulate cortex 


Conflict of Interest

The authors declare that they have no competing interests.


  1. Auvray M, Myin E et al (2010) The sensory-discriminative and affective-motivational aspects of pain. Neurosci Biobehav Rev 34(2):214–23CrossRefPubMedGoogle Scholar
  2. Brennan TJ, Vandermeulen EP et al (1996) Characterization of a rat model of incisional pain. Pain 64(3):493–501CrossRefPubMedGoogle Scholar
  3. Cao H, Zang KK et al (2014a) Inhibition of p38 mitogen-activated protein kinase activation in the rostral anterior cingulate cortex attenuates pain-related negative emotion in rats. Brain Res Bull 107:79–88CrossRefPubMedGoogle Scholar
  4. Cao H, Ren WH et al (2012) Activation of glycine site and GluN2B subunit of NMDA receptors is necessary for ERK/CREB signaling cascade in rostral anterior cingulate cortex in rats: implications for affective pain. Neurosci Bull 28(1):77–87CrossRefPubMedGoogle Scholar
  5. Cao H, Gao YJ et al (2009) Activation of extracellular signal-regulated kinase in the anterior cingulate cortex contributes to the induction and expression of affective pain. J Neurosci 29(10):3307–21PubMedCentralCrossRefPubMedGoogle Scholar
  6. Cao W, Duan J et al (2014b) Early enriched environment induces an increased conversion of proBDNF to BDNF in the adult rat’s hippocampus. Behav Brain Res 265:76–83CrossRefPubMedGoogle Scholar
  7. Chaplan SR, Bach FW et al (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63CrossRefPubMedGoogle Scholar
  8. Chau PL (2010) New insights into the molecular mechanisms of general anaesthetics. Br J Pharmacol 161(2):288–307PubMedCentralCrossRefPubMedGoogle Scholar
  9. Dai RP, Li CQ et al (2011) Biphasic activation of extracellular signal-regulated kinase in anterior cingulate cortex distinctly regulates the development of pain-related anxiety and mechanical hypersensitivity in rats after incision. Anesthesiology 115(3):604–13CrossRefPubMedGoogle Scholar
  10. Dai Y, Iwata K et al (2002) Phosphorylation of extracellular signal-regulated kinase in primary afferent neurons by noxious stimuli and its involvement in peripheral sensitization. J Neurosci 22(17):7737–45PubMedGoogle Scholar
  11. Dubuisson D, Dennis SG (1977) The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4(2):161–74CrossRefPubMedGoogle Scholar
  12. Franks NP (2006) Molecular targets underlying general anaesthesia. Br J Pharmacol 147(Suppl 1):S72–81PubMedCentralPubMedGoogle Scholar
  13. Gan TJ, Habib AS et al (2014) Incidence, patient satisfaction, and perceptions of post-surgical pain: results from a US national survey. Curr Med Res Opin 30(1):149–60CrossRefPubMedGoogle Scholar
  14. Gao YJ, Ji RR (2009) c-Fos and pERK, which is a better marker for neuronal activation and central sensitization after noxious stimulation and tissue injury? Open Pain J 2:11–17PubMedCentralCrossRefPubMedGoogle Scholar
  15. Gao YJ, Ren WH et al (2004) Contributions of the anterior cingulate cortex and amygdala to pain- and fear-conditioned place avoidance in rats. Pain 110(1-2):343–53CrossRefPubMedGoogle Scholar
  16. Grasshoff C, Antkowiak B (2004) Propofol and sevoflurane depress spinal neurons in vitro via different molecular targets. Anesthesiology 101(5):1167–76CrossRefPubMedGoogle Scholar
  17. Hao S, Takahata O et al (2002) Sevoflurane suppresses noxious stimulus-evoked expression of Fos-like immunoreactivity in the rat spinal cord via activation of endogenous opioid systems. Life Sci 71(5):571–80CrossRefPubMedGoogle Scholar
  18. Kubota I, Tsuboi Y et al (2007) Modulation of neuronal activity in CNS pain pathways following propofol administration in rats: Fos and EEG analysis. Exp Brain Res 179(2):181–90CrossRefPubMedGoogle Scholar
  19. Le BD, Gozariu M et al (2001) Animal models of nociception. Pharmacol Rev 53(4):597–652Google Scholar
  20. Lei LG, Zhang YQ et al (2004) Pain-related aversion and Fos expression in the central nervous system in rats. Neuroreport 15(1):67–71CrossRefPubMedGoogle Scholar
  21. Li CQ, Zhang JW et al (2010) Surgical incision induces anxiety-like behavior and amygdala sensitization: effects of morphine and gabapentin. Pain Res Treat 2010:705874PubMedCentralPubMedGoogle Scholar
  22. Li F, Cao WY et al (2012) A simple method for detection of food foraging behavior in the rat: involvement of NMDA and dopamine receptors in the behavior. Neuroscience 205:73–80CrossRefPubMedGoogle Scholar
  23. Lorentzen V, Hermansen IL et al (2012) A prospective analysis of pain experience, beliefs and attitudes, and pain management of a cohort of Danish surgical patients. Eur J Pain 16(2):278–88CrossRefPubMedGoogle Scholar
  24. Luo YW, Xu Y et al (2014) Insulin-like growth factor 2 mitigates depressive behavior in a rat model of chronic stress. Neuropharmacology 89C:318–324Google Scholar
  25. May A (2008) Chronic pain may change the structure of the brain. Pain 137(1):7–15CrossRefPubMedGoogle Scholar
  26. Petrenko AB, Yamakura T et al (2014) Defining the role of NMDA receptors in anesthesia: are we there yet? Eur J Pharmacol 723:29–37CrossRefPubMedGoogle Scholar
  27. Pogatzki EM, Urban MO et al (2002) Role of the rostral medial medulla in the development of primary and secondary hyperalgesia after incision in the rat. Anesthesiology 96(5):1153–60CrossRefPubMedGoogle Scholar
  28. Price DD (2000) Psychological and neural mechanisms of the affective dimension of pain. Science 288(5472):1769–72CrossRefPubMedGoogle Scholar
  29. Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463(1-3):3–33CrossRefPubMedGoogle Scholar
  30. Shin SW, Cho AR et al (2010) Maintenance anaesthetics during remifentanil-based anaesthesia might affect postoperative pain control after breast cancer surgery. Br J Anaesth 105(5):661–7CrossRefPubMedGoogle Scholar
  31. Stabernack C, Sonner JM et al (2003) Spinal N-methyl-d-aspartate receptors may contribute to the immobilizing action of isoflurane. Anesth Analg 96(1):102–7, table of contentsPubMedGoogle Scholar
  32. Sukhotinsky I, Hopkins DA et al (2005) Movement suppression during anesthesia: neural projections from the mesopontine tegmentum to areas involved in motor control. J Comp Neurol 489(4):425–48CrossRefPubMedGoogle Scholar
  33. Sukhotinsky I, Reiner K et al (2006) Projections from the mesopontine tegmental anesthesia area to regions involved in pain modulation. J Chem Neuroanat 32(2-4):159–78CrossRefPubMedGoogle Scholar
  34. Sukhotinsky I, Zalkind V et al (2007) Neural pathways associated with loss of consciousness caused by intracerebral microinjection of GABA A-active anesthetics. Eur J Neurosci 25(5):1417–36CrossRefPubMedGoogle Scholar
  35. Takasusuki T, Yamaguchi S et al (2013) Effects of general anesthetics on substance P release and c-Fos expression in the spinal dorsal horn. Anesthesiology 119(2):433–42PubMedCentralCrossRefPubMedGoogle Scholar
  36. Tang J, Gibson SJ (2005) A psychophysical evaluation of the relationship between trait anxiety, pain perception, and induced state anxiety. J Pain 6(9):612–9CrossRefPubMedGoogle Scholar
  37. Thompson SA, Wafford K (2001) Mechanism of action of general anaesthetics—new information from molecular pharmacology. Curr Opin Pharmacol 1(1):78–83CrossRefPubMedGoogle Scholar
  38. Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2(2):322–8PubMedCentralCrossRefPubMedGoogle Scholar
  39. Wei F, Zhuo M (2008) Activation of Erk in the anterior cingulate cortex during the induction and expression of chronic pain. Mol Pain 4:28PubMedCentralCrossRefPubMedGoogle Scholar
  40. Wheeler-Aceto H, Porreca F et al (1990) The rat paw formalin test: comparison of noxious agents. Pain 40(2):229–38CrossRefPubMedGoogle Scholar
  41. White JP, Cibelli M et al (2010) Sensitization of the transient receptor potential vanilloid type 1 ion channel by isoflurane or sevoflurane does not result in extracellular signal-regulated kinase 1/2 activation in rat spinal dorsal horn neurons. Neuroscience 166(2):633–8CrossRefPubMedGoogle Scholar
  42. Xie YF, Huo FQ et al (2009) Cerebral cortex modulation of pain. Acta Pharmacol Sin 30(1):31–41PubMedCentralCrossRefPubMedGoogle Scholar
  43. Yang T, Zhuang L et al (2012) Xenon and sevoflurane provide analgesia during labor and fetal brain protection in a perinatal rat model of hypoxia-ischemia. PLoS One 7(5):e37020PubMedCentralCrossRefPubMedGoogle Scholar
  44. Ying SW, Goldstein PA (2005) Propofol suppresses synaptic responsiveness of somatosensory relay neurons to excitatory input by potentiating GABA(A) receptor chloride channels. Mol Pain 1:2PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of AnesthesiologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
  2. 2.Department of Anatomy and Neurobiology, Xiangya School of MedicineCentral South UniversityChangshaChina
  3. 3.School of Pharmacy and Medical Sciences, Division of Health SciencesUniversity of South AustraliaAdelaideAustralia

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