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CRF regulates pain sensation by enhancement of corticoaccumbal excitatory synaptic transmission

Molecular Psychiatry (2024)Cite this article

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Abstract

Both peripheral and central corticotropin-releasing factor (CRF) systems have been implicated in regulating pain sensation. However, compared with the peripheral, the mechanisms underlying central CRF system in pain modulation have not yet been elucidated, especially at the neural circuit level. The corticoaccumbal circuit, a structure rich in CRF receptors and CRF-positive neurons, plays an important role in behavioral responses to stressors including nociceptive stimuli. The present study was designed to investigate whether and how CRF signaling in this circuit regulated pain sensation under physiological and pathological pain conditions. Our studies employed the viral tracing and circuit-, and cell-specific electrophysiological methods to label the CRF-containing circuit from the medial prefrontal cortex to the nucleus accumbens shell (mPFCCRF-NAcS) and record its neuronal propriety. Combining optogenetic and chemogenetic manipulation, neuropharmacological methods, and behavioral tests, we were able to precisely manipulate this circuit and depict its role in regulation of pain sensation. The current study found that the CRF signaling in the NAc shell (NAcS), but not NAc core, was necessary and sufficient for the regulation of pain sensation under physiological and pathological pain conditions. This process was involved in the CRF-mediated enhancement of excitatory synaptic transmission in the NAcS. Furthermore, we demonstrated that the mPFCCRF neurons monosynaptically connected with the NAcS neurons. Chronic pain increased the protein level of CRF in NAcS, and then maintained the persistent NAcS neuronal hyperactivity through enhancement of this monosynaptic excitatory connection, and thus sustained chronic pain behavior. These findings reveal a novel cell- and circuit-based mechanistic link between chronic pain and the mPFCCRF → NAcS circuit and provide a potential new therapeutic target for chronic pain.

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Fig. 1: The NAcS CRF signaling regulates pain sensation.
Fig. 2: CRF enhances excitatory synaptic transmission and neuronal excitability in the NAcS.
Fig. 3: mPFCCRF→NAcS circuit is required for CCI-induced hyperalgesia.
Fig. 4: The sufficient role of the mPFCCRF→NAcS circuit in pain sensation regulation.
Fig. 5: Identifying monosynaptic connection in the mPFCCRF→NAcS circuit and its functional alteration in chronic neuropathic pain.
Fig. 6: The role of NAcS-receiving neurons innervated by mPFC CRF-containing neurons in pain sensation regulation.

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References

  1. Walsh JJ, Friedman AK, Sun H, Heller EA, Ku SM, Juarez B, et al. Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nat Neurosci. 2014;17:27–29.

    Article  CAS  PubMed  Google Scholar 

  2. Bale TL, Vale WW. CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol. 2004;44:525–57.

    Article  CAS  PubMed  Google Scholar 

  3. Henckens MJ, Deussing JM, Chen A. Region-specific roles of the corticotropin-releasing factor-urocortin system in stress. Nat Rev Neurosci. 2016;17:636–51.

    Article  CAS  PubMed  Google Scholar 

  4. Lv Y, Chen P, Shan QH, Qin XY, Qi XH, Zhou JN. Regulation of Cued Fear Expression via Corticotropin-Releasing-Factor Neurons in the Ventral Anteromedial Thalamic Nucleus. Neurosci Bull. 2021;37:217–28.

    Article  CAS  PubMed  Google Scholar 

  5. Engelke DS, Zhang XO, O’Malley JJ, Fernandez-Leon JA, Li S, Kirouac GJ, et al. A hypothalamic-thalamostriatal circuit that controls approach-avoidance conflict in rats. Nat Commun. 2021;12:2517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Koob GF. The role of CRF and CRF-related peptides in the dark side of addiction. Brain Res. 2010;1314:3–14.

    Article  CAS  PubMed  Google Scholar 

  7. Binder EB, Nemeroff CB. The CRF system, stress, depression and anxiety-insights from human genetic studies. Mol Psychiatry. 2010;15:574–88.

    Article  CAS  PubMed  Google Scholar 

  8. Chen P, Lou S, Huang ZH, Wang Z, Shan QH, Wang Y, et al. Prefrontal Cortex Corticotropin-Releasing Factor Neurons Control Behavioral Style Selection under Challenging Situations. Neuron. 2020;106:301–15. e307

    Article  CAS  PubMed  Google Scholar 

  9. Abdallah CG, Geha P. Chronic Pain and Chronic Stress: Two Sides of the Same Coin? Chronic Stress. 2017;1:2470547017704763.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Yu W, Caira CM, Del RRSN, Moseley GA, Kash TL. Corticotropin-releasing factor neurons in the bed nucleus of the stria terminalis exhibit sex-specific pain encoding in mice. Sci Rep. 2021;11:12500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bourbia N, Ansah OB, Pertovaara A. Corticotropin-releasing factor in the rat amygdala differentially influences sensory-discriminative and emotional-like pain response in peripheral neuropathy. J Pain. 2010;11:1461–71.

    Article  CAS  PubMed  Google Scholar 

  12. McLean SA, Williams DA, Stein PK, Harris RE, Lyden AK, Whalen G, et al. Cerebrospinal fluid corticotropin-releasing factor concentration is associated with pain but not fatigue symptoms in patients with fibromyalgia. Neuropsychopharmacology. 2006;31:2776–82.

    Article  CAS  PubMed  Google Scholar 

  13. Larauche M, Moussaoui N, Biraud M, Bae WK, Duboc H, Million M, et al. Brain corticotropin-releasing factor signaling: Involvement in acute stress-induced visceral analgesia in male rats. Neurogastroenterol Motil. 2019;31:e13489.

    Article  PubMed  Google Scholar 

  14. Lariviere WR, Melzack R. The role of corticotropin-releasing factor in pain and analgesia. Pain. 2000;84:1–12.

    Article  CAS  PubMed  Google Scholar 

  15. Vit JP, Clauw DJ, Moallem T, Boudah A, Ohara PT, Jasmin L. Analgesia and hyperalgesia from CRF receptor modulation in the central nervous system of Fischer and Lewis rats. Pain. 2006;121:241–60.

    Article  CAS  PubMed  Google Scholar 

  16. Williams DW Jr., Lipton JM, Giesecke AH Jr. Influence of centrally administered peptides on ear withdrawal from heat in the rabbit. Peptides. 1986;7:1095–1100.

    Article  CAS  PubMed  Google Scholar 

  17. Thompson JM, Neugebauer V. Cortico-limbic pain mechanisms. Neurosci Lett. 2019;702:15–23.

    Article  CAS  PubMed  Google Scholar 

  18. Zhu X, Zhou W, Jin Y, Tang H, Cao P, Mao Y, et al. A Central Amygdala Input to the Parafascicular Nucleus Controls Comorbid Pain in Depression. Cell Rep. 2019;29:3847–58. e3845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhou W, Jin Y, Meng Q, Zhu X, Bai T, Tian Y, et al. A neural circuit for comorbid depressive symptoms in chronic pain. Nat Neurosci. 2019;22:1649–58.

    Article  CAS  PubMed  Google Scholar 

  20. Takahashi D, Asaoka Y, Kimura K, Hara R, Arakaki S, Sakasai K, et al. Tonic Suppression of the Mesolimbic Dopaminergic System by Enhanced Corticotropin-Releasing Factor Signaling Within the Bed Nucleus of the Stria Terminalis in Chronic Pain Model Rats. J Neurosci. 2019;39:8376–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Castro DC, Bruchas MR. A Motivational and Neuropeptidergic Hub: Anatomical and Functional Diversity within the Nucleus Accumbens Shell. Neuron. 2019;102:529–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu D, Tang QQ, Yin C, Song Y, Liu Y, Yang JX, et al. Brain-derived neurotrophic factor-mediated projection-specific regulation of depressive-like and nociceptive behaviors in the mesolimbic reward circuitry. Pain. 2018;159:175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. An K, Zhao H, Miao Y, Xu Q, Li YF, Ma YQ, et al. A circadian rhythm-gated subcortical pathway for nighttime-light-induced depressive-like behaviors in mice. Nat Neurosci. 2020;23:869–80.

    Article  CAS  PubMed  Google Scholar 

  24. Baliki MN, Geha PY, Fields HL, Apkarian AV. Predicting value of pain and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain. Neuron. 2010;66:149–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Harris HN, Peng YB. Evidence and explanation for the involvement of the nucleus accumbens in pain processing. Neural Regen Res. 2020;15:597–605.

    Article  CAS  PubMed  Google Scholar 

  26. Guo F, Du Y, Qu FH, Lin SD, Chen Z, Zhang SH. Dissecting the Neural Circuitry for Pain Modulation and Chronic Pain: Insights from Optogenetics. Neurosci Bull. 2022;38:440–52.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhang H, Qian YL, Li C, Liu D, Wang L, Wang XY, et al. Brain-Derived Neurotrophic Factor in the Mesolimbic Reward Circuitry Mediates Nociception in Chronic Neuropathic Pain. Biol Psychiatry. 2017;82:608–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Makary MM, Polosecki P, Cecchi GA, DeAraujo IE, Barron DS, Constable TR, et al. Loss of nucleus accumbens low-frequency fluctuations is a signature of chronic pain. Proc Natl Acad Sci USA. 2020;117:10015–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Seminowicz DA, Remeniuk B, Krimmel SR, Smith MT, Barrett FS, Wulff AB, et al. Pain-related nucleus accumbens function: modulation by reward and sleep disruption. Pain. 2019;160:1196–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mallory GW, Abulseoud O, Hwang SC, Gorman DA, Stead SM, Klassen BT, et al. The nucleus accumbens as a potential target for central poststroke pain. Mayo Clin Proc. 2012;87:1025–31.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Jing PB, Chen XH, Lu HJ, Gao YJ, Wu XB. Enhanced function of NR2C/2D-containing NMDA receptor in the nucleus accumbens contributes to peripheral nerve injury-induced neuropathic pain and depression in mice. Mol Pain. 2022;18:17448069211053255.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Faramarzi G, Zendehdel M, Haghparast A. D1- and D2-like dopamine receptors within the nucleus accumbens contribute to stress-induced analgesia in formalin-related pain behaviours in rats. Eur J Pain. 2016;20:1423–32.

    Article  CAS  PubMed  Google Scholar 

  33. Schank JR, Nelson BS, Damadzic R, Tapocik JD, Yao M, King CE, et al. Neurokinin-1 receptor antagonism attenuates neuronal activity triggered by stress-induced reinstatement of alcohol seeking. Neuropharmacology. 2015;99:106–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Smith NK, Kondev V, Hunt TR, Grueter BA. Neuropeptide Y modulates excitatory synaptic transmission and promotes social behavior in the mouse nucleus accumbens. Neuropharmacology. 2022;217:109201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Morales-Mulia S, Magdaleno-Madrigal VM, Nicolini H, Genis-Mendoza A, Morales-Mulia M. Orexin-A up-regulates dopamine D2 receptor and mRNA in the nucleus accumbens Shell. Mol Biol Rep. 2020;47:9689–97.

    Article  CAS  PubMed  Google Scholar 

  36. Xia SH, Yu J, Huang X, Sesack SR, Huang YH, Schlüter OM, et al. Cortical and Thalamic Interaction with Amygdala-to-Accumbens Synapses. J Neurosci. 2020;40:7119–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Baumgartner HM, Schulkin J, Berridge KC. Activating Corticotropin-Releasing Factor Systems in the Nucleus Accumbens, Amygdala, and Bed Nucleus of Stria Terminalis: Incentive Motivation or Aversive Motivation? Biol Psychiatry. 2021;89:1162–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Marcinkiewcz CA, Prado MM, Isaac SK, Marshall A, Rylkova D, Bruijnzeel AW. Corticotropin-releasing factor within the central nucleus of the amygdala and the nucleus accumbens shell mediates the negative affective state of nicotine withdrawal in rats. Neuropsychopharmacology. 2009;34:1743–52.

    Article  CAS  PubMed  Google Scholar 

  39. Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, et al. Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature. 2012;490:402–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Novoa J, Rivero CJ, Pérez-Cardona EU, Freire-Arvelo JA, Zegers J, Yarur HE, et al. Social isolation of adolescent male rats increases anxiety and K(+) -induced dopamine release in the nucleus accumbens: Role of CRF-R1. Eur J Neurosci. 2021;54:4888–905.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kai Y, Li Y, Sun T, Yin W, Mao Y, Li J, et al. A medial prefrontal cortex-nucleus acumens corticotropin-releasing factor circuitry for neuropathic pain-increased susceptibility to opioid reward. Transl Psychiatry. 2018;8:100.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Chen YW, Rada PV, Bützler BP, Leibowitz SF, Hoebel BG. Corticotropin-releasing factor in the nucleus accumbens shell induces swim depression, anxiety, and anhedonia along with changes in local dopamine/acetylcholine balance. Neuroscience. 2012;206:155–66.

    Article  CAS  PubMed  Google Scholar 

  43. Watanabe M, Narita M. Brain Reward Circuit and Pain. Adv Exp Med Biol. 2018;1099:201–10.

    Article  CAS  PubMed  Google Scholar 

  44. Serafini RA, Pryce KD, Zachariou V. The Mesolimbic Dopamine System in Chronic Pain and Associated Affective Comorbidities. Biol Psychiatry. 2020;87:64–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Elman I, Borsook D. Common Brain Mechanisms of Chronic Pain and Addiction. Neuron. 2016;89:11–36.

    Article  CAS  PubMed  Google Scholar 

  46. Ambroggi F, Ghazizadeh A, Nicola SM, Fields HL. Roles of nucleus accumbens core and shell in incentive-cue responding and behavioral inhibition. J Neurosci. 2011;31:6820–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lisman J, Cooper K, Sehgal M, Silva AJ. Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability. Nat Neurosci. 2018;21:309–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bradley C, Nydam AS, Dux PE, Mattingley JB. State-dependent effects of neural stimulation on brain function and cognition. Nat Rev Neurosci. 2022;23:459–75.

    Article  CAS  PubMed  Google Scholar 

  49. Authement ME, Langlois LD, Shepard RD, Browne CA, Lucki I, Kassis H, et al. A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress. Sci Signal. 2018;11:eaan6480.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci. 2011;12:623–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Itoga CA, Chen Y, Fateri C, Echeverry PA, Lai JM, Delgado J, et al. New viral-genetic mapping uncovers an enrichment of corticotropin-releasing hormone-expressing neuronal inputs to the nucleus accumbens from stress-related brain regions. J Comp Neurol. 2019;527:2474–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Heidbreder CA, Groenewegen HJ. The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics. Neurosci Biobehav Rev. 2003;27:555–79.

    Article  PubMed  Google Scholar 

  53. Wang H, Qian T, Zhao Y, Zhuo Y, Wu C, Osakada T, et al. A tool kit of highly selective and sensitive genetically encoded neuropeptide sensors. Science. 2023;382:eabq8173.

    Article  CAS  PubMed  Google Scholar 

  54. Xu X, Holmes TC, Luo MH, Beier KT, Horwitz GD, Zhao F, et al. Viral Vectors for Neural Circuit Mapping and Recent Advances in Trans-synaptic Anterograde Tracers. Neuron. 2020;107:1029–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hoover WB, Vertes RP. Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct Funct. 2007;212:149–79.

    Article  PubMed  Google Scholar 

  56. Dedic N, Kühne C, Jakovcevski M, Hartmann J, Genewsky AJ, Gomes KS, et al. Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety. Nat Neurosci. 2018;21:803–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sanford CA, Soden ME, Baird MA, Miller SM, Schulkin J, Palmiter RD, et al. A Central Amygdala CRF Circuit Facilitates Learning about Weak Threats. Neuron. 2017;93:164–78.

    Article  CAS  PubMed  Google Scholar 

  58. Chen W, Taché Y, Marvizón JC. Corticotropin-Releasing Factor in the Brain and Blocking Spinal Descending Signals Induce Hyperalgesia in the Latent Sensitization Model of Chronic Pain. Neuroscience. 2018;381:149–58.

    Article  CAS  PubMed  Google Scholar 

  59. Rouwette T, Klemann K, Gaszner B, Scheffer GJ, Roubos EW, Scheenen WJ, et al. Differential responses of corticotropin-releasing factor and urocortin 1 to acute pain stress in the rat brain. Neuroscience. 2011;183:15–24.

    Article  CAS  PubMed  Google Scholar 

  60. Holland PR, Bartsch T. Involvement of corticotrophin-releasing factor and orexin-A in chronic migraine and medication overuse headache: findings from cerebrospinal fluid. Cephalalgia. 2008;28:681–2.

    Article  CAS  PubMed  Google Scholar 

  61. Cabot PJ, Carter L, Gaiddon C, Zhang Q, Schäfer M, Loeffler JP, et al. Immune cell-derived beta-endorphin. Production, release, and control of inflammatory pain in rats. J Clin Invest. 1997;100:142–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Andreoli M, Marketkar T, Dimitrov E. Contribution of amygdala CRF neurons to chronic pain. Exp Neurol. 2017;298:1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mazzitelli M, Yakhnitsa V, Neugebauer B, Neugebauer V. Optogenetic manipulations of CeA-CRF neurons modulate pain- and anxiety-like behaviors in neuropathic pain and control rats. Neuropharmacology. 2022;210:109031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kita A, Imano K, Nakamura H. Involvement of corticotropin-releasing factor in the antinociception produced by interleukin-1 in mice. Eur J Pharmacol. 1993;237:317–22.

    Article  CAS  PubMed  Google Scholar 

  65. Deussing JM, Chen A. The Corticotropin-Releasing Factor Family: Physiology of the Stress Response. Physiological reviews. 2018;98:2225–86.

    Article  CAS  PubMed  Google Scholar 

  66. Vita N, Laurent P, Lefort S, Chalon P, Lelias JM, Kaghad M, et al. Primary structure and functional expression of mouse pituitary and human brain corticotrophin releasing factor receptors. FEBS Lett. 1993;335:1–5.

    Article  CAS  PubMed  Google Scholar 

  67. Bale TL, Picetti R, Contarino A, Koob GF, Vale WW, Lee KF. Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior. J Neurosci. 2002;22:193–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bale TL, Contarino A, Smith GW, Chan R, Gold LH, Sawchenko PE, et al. Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat Genet. 2000;24:410–4.

    Article  CAS  PubMed  Google Scholar 

  69. Kishimoto T, Radulovic J, Radulovic M, Lin CR, Schrick C, Hooshmand F, et al. Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. Nat Genet. 2000;24:415–9.

    Article  CAS  PubMed  Google Scholar 

  70. Prouty EW, Waterhouse BD, Chandler DJ. Corticotropin releasing factor dose-dependently modulates excitatory synaptic transmission in the noradrenergic nucleus locus coeruleus. Eur J Neurosci. 2017;45:712–22.

    Article  PubMed  Google Scholar 

  71. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139:267–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kuner R, Flor H. Structural plasticity and reorganisation in chronic pain. Nat Rev Neurosci. 2016;18:20–30.

    Article  PubMed  Google Scholar 

  73. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895–926.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Neugebauer V, Mazzitelli M, Cragg B, Ji G, Navratilova E, Porreca F. Amygdala, neuropeptides, and chronic pain-related affective behaviors. Neuropharmacology. 2020;170:108052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lu VB, Biggs JE, Stebbing MJ, Balasubramanyan S, Todd KG, Lai AY, et al. Brain-derived neurotrophic factor drives the changes in excitatory synaptic transmission in the rat superficial dorsal horn that follow sciatic nerve injury. J Physiol. 2009;587:1013–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yang S, Chang MC. Chronic Pain: Structural and Functional Changes in Brain Structures and Associated Negative Affective States. Int J Mol Sci. 2019;20:3130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Holahan MR, Kalin NH, Kelley AE. Microinfusion of corticotropin-releasing factor into the nucleus accumbens shell results in increased behavioral arousal and oral motor activity. Psychopharmacology. 1997;130:189–96.

    Article  CAS  PubMed  Google Scholar 

  78. Bryce CA, Floresco SB. Alterations in effort-related decision-making induced by stimulation of dopamine D(1), D(2), D(3), and corticotropin-releasing factor receptors in nucleus accumbens subregions. Psychopharmacology. 2019;236:2699–712.

    Article  CAS  PubMed  Google Scholar 

  79. Lemos JC, Shin JH, Alvarez VA. Striatal Cholinergic Interneurons Are a Novel Target of Corticotropin Releasing Factor. J Neurosci. 2019;39:5647–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kono J, Konno K, Talukder AH, Fuse T, Abe M, Uchida K, et al. Distribution of corticotropin-releasing factor neurons in the mouse brain: a study using corticotropin-releasing factor-modified yellow fluorescent protein knock-in mouse. Brain Struct Funct. 2017;222:1705–32.

    Article  CAS  PubMed  Google Scholar 

  81. Justice NJ, Yuan ZF, Sawchenko PE, Vale W. Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice: implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. J Comp Neurol. 2008;511:479–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Islam J, Kc E, Kim S, Kim HK, Park YS. Stimulating GABAergic Neurons in the Nucleus Accumbens Core Alters the Trigeminal Neuropathic Pain Responses in a Rat Model of Infraorbital Nerve Injury. Int J Mol Sci. 2021;22:8421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yao L, Rong Y, Ma X, Li H, Deng D, Chen Y, et al. Extrasynaptic NMDA Receptors Bidirectionally Modulate Intrinsic Excitability of Inhibitory Neurons. J Neurosci. 2022;42:3066–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Pan G, Chen Z, Zheng H, Zhang Y, Xu H, Bu G, et al. Compensatory Mechanisms Modulate the Neuronal Excitability in a Kainic Acid-Induced Epilepsy Mouse Model. Front Neural Circuits. 2018;12:48.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Huang YH, Lin Y, Brown TE, Han MH, Saal DB, Neve RL, et al. CREB modulates the functional output of nucleus accumbens neurons: a critical role of N-methyl-D-aspartate glutamate receptor (NMDAR) receptors. J Biol Chem. 2008;283:2751–60.

    Article  CAS  PubMed  Google Scholar 

  86. Hu XT, White FJ. Glutamate receptor regulation of rat nucleus accumbens neurons in vivo. Synapse. 1996;23:208–18.

    Article  CAS  PubMed  Google Scholar 

  87. Cooper DC, White FJ. L-type calcium channels modulate glutamate-driven bursting activity in the nucleus accumbens in vivo. Brain Res. 2000;880:212–8.

    Article  CAS  PubMed  Google Scholar 

  88. Qi C, Guo B, Ren K, Yao H, Wang M, Sun T, et al. Chronic inflammatory pain decreases the glutamate vesicles in presynaptic terminals of the nucleus accumbens. Mol Pain. 2018;14:1744806918781259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ziółkowska B. The Role of Mesostriatal Dopamine System and Corticostriatal Glutamatergic Transmission in Chronic Pain. Brain Sci. 2021;11:1311.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Zegers-Delgado J, Aguilera-Soza A, Calderón F, Davidson H, Verbel-Vergara D, Yarur HE, et al. Type 1 Corticotropin-Releasing Factor Receptor Differentially Modulates Neurotransmitter Levels in the Nucleus Accumbens of Juvenile versus Adult Rats. Int J Mol Sci. 2022;23:1080.

    Article  Google Scholar 

  91. Park BY, Lee JJ, Kim HJ, Woo CW, Park H. A neuroimaging marker for predicting longitudinal changes in pain intensity of subacute back pain based on large-scale brain network interactions. Sci Rep. 2020;10:17392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Löffler M, Levine SM, Usai K, Desch S, Kandić M, Nees F, et al. Corticostriatal circuits in the transition to chronic back pain: The predictive role of reward learning. Cell Rep Med. 2022;3:100677.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Baliki MN, Petre B, Torbey S, Herrmann KM, Huang L, Schnitzer TJ, et al. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat Neurosci. 2012;15:1117–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Waselus M, Van Bockstaele EJ. Co-localization of corticotropin-releasing factor and vesicular glutamate transporters within axon terminals of the rat dorsal raphe nucleus. Brain Res. 2007;1174:53–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Arrigoni E, Saper CB. What optogenetic stimulation is telling us (and failing to tell us) about fast neurotransmitters and neuromodulators in brain circuits for wake-sleep regulation. Curr Opin Neurobiol. 2014;29:165–71.

    Article  CAS  PubMed  Google Scholar 

  96. Bartfai T, Iverfeldt K, Fisone G, Serfözö P. Regulation of the release of coexisting neurotransmitters. Annu Rev Pharmacol Toxicol. 1988;28:285–310.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Li Yang, Dong-Yu Zhou, Wei Zheng and Prof. Cheng Xiao for technical supports. The present study was supported by the National Key R&D Program of China—the Sci-Tech Innovation 2030 Major Project (2021ZD0203100), the National Natural Science Foundation of China (82130033, 82293641, 31970937, 82271255, 82101315 and 82271263); Jiangsu Province Innovative and Entrepreneurial Team Program, the Key Project of Nature Science Foundation of Jiangsu Education Department (22KJA320006); the Innovation and Entrepreneurship Program of Xuzhou Medical University (2021CXFUZX002), China Postdoctoral Science Foundation (2022M710771 and 2022M722676), the Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX21_2704); the Yangfan Plan of Shanghai Science and Technology Commission (No. 22YF1439600); the China Postdoctoral Science Foundation (No. 2022M710771); the National Natural Science Foundation of China (No. 82201372).

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  1. These authors contributed equally: Weinan Zhao, Yu-Mei Yu, Xiao-Yi Wang.

Authors and Affiliations

  1. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China

    Weinan Zhao, Yu-Mei Yu, Xiao-Yi Wang, Sun-Hui Xia, Yu Ma, Huimei Tang, Mingshu Tao, He Li, Zheng Xu, Jun-Xia Yang, Peng Wu, Hongxing Zhang, Hai-Lei Ding & Jun-Li Cao

  2. Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China

    Weinan Zhao, Yu-Mei Yu, Xiao-Yi Wang, Sun-Hui Xia, Yu Ma, Huimei Tang, Mingshu Tao, He Li, Zheng Xu, Jun-Xia Yang, Peng Wu, Hongxing Zhang, Hai-Lei Ding & Jun-Li Cao

  3. NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China

    Weinan Zhao, Yu-Mei Yu, Sun-Hui Xia, Yu Ma, Huimei Tang, Mingshu Tao, He Li, Zheng Xu, Jun-Xia Yang, Peng Wu, Hongxing Zhang, Hai-Lei Ding & Jun-Li Cao

  4. Department of Anesthesiology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, Jiangsu, China

    Xiao-Yi Wang

  5. Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China

    Jun-Li Cao

Authors
  1. Weinan Zhao
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  2. Yu-Mei Yu
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  3. Xiao-Yi Wang
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  4. Sun-Hui Xia
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  5. Yu Ma
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  6. Huimei Tang
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  7. Mingshu Tao
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  8. He Li
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  9. Zheng Xu
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  10. Jun-Xia Yang
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  11. Peng Wu
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  12. Hongxing Zhang
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  13. Hai-Lei Ding
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  14. Jun-Li Cao
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Contributions

W.Z., Y.-M.Y., X.-Y.W., S.-H.X., Y.M., H.T., M.T., H.L., Z.X., H.Z., J.-L.C., and H.-L.D. initiated and designed the research. W.Z., S.-H.X., and J.-L.C. wrote the manuscript. W.Z., X.-Y.W., Y.M., Y.-M.Y., H.T., M.T., H.L., P.W. and J.-X.Y. performed all experiments and analyzed and interpreted the results. All the authors approved the submission.

Corresponding authors

Correspondence to Hai-Lei Ding or Jun-Li Cao.

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Zhao, W., Yu, YM., Wang, XY. et al. CRF regulates pain sensation by enhancement of corticoaccumbal excitatory synaptic transmission. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02488-7

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  • DOI: https://doi.org/10.1038/s41380-024-02488-7

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