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Impaired Ventrolateral Periaqueductal Gray-Ventral Tegmental area Pathway Contributes to Chronic Pain-Induced Depression-Like Behavior in Mice

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Abstract

Chronic pain conditions within clinical populations are correlated with a high incidence of depression, and researchers have reported their high rate of comorbidity. Clinically, chronic pain worsens the prevalence of depression, and depression increases the risk of chronic pain. Individuals suffering from chronic pain and depression respond poorly to available medications, and the mechanisms underlying the comorbidity of chronic pain and depression remain unknown. We used spinal nerve ligation (SNL) in a mouse model to induce comorbid pain and depression. We combined behavioral tests, electrophysiological recordings, pharmacological manipulation, and chemogenetic approaches to investigate the neurocircuitry mechanisms of comorbid pain and depression. SNL elicited tactile hypersensitivity and depression-like behavior, accompanied by increased and decreased glutamatergic transmission in dorsal horn neurons and midbrain ventrolateral periaqueductal gray (vlPAG) neurons, respectively. Intrathecal injection of lidocaine, a sodium channel blocker, and gabapentin ameliorated SNL-induced tactile hypersensitivity and neuroplastic changes in the dorsal horn but not depression-like behavior and neuroplastic alterations in the vlPAG. Pharmacological lesion of vlPAG glutamatergic neurons induced tactile hypersensitivity and depression-like behavior. Chemogenetic activation of the vlPAG-rostral ventromedial medulla (RVM) pathway ameliorated SNL-induced tactile hypersensitivity but not SNL-elicited depression-like behavior. However, chemogenetic activation of the vlPAG-ventral tegmental area (VTA) pathway alleviated SNL-produced depression-like behavior but not SNL-induced tactile hypersensitivity. Our study demonstrated that the underlying mechanisms of comorbidity in which the vlPAG acts as a gating hub for transferring pain to depression. Tactile hypersensitivity could be attributed to dysfunction of the vlPAG-RVM pathway, while impairment of the vlPAG-VTA pathway contributed to depression-like behavior.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Kroenke K (2003) Patients presenting with somatic complaints: epidemiology, psychiatric comorbidity and management. Int J Methods Psychiatr Res 12(1):34–43

    Article  PubMed  Google Scholar 

  2. Spitzer RL et al (1995) Health-related quality of life in primary care patients with mental disorders Results from the PRIME-MD 1000 Study. JAMA 274(19):1511–7

    Article  CAS  PubMed  Google Scholar 

  3. Bair MJ et al (2003) Depression and pain comorbidity: a literature review. Arch Intern Med 163(20):2433–2445

    Article  PubMed  Google Scholar 

  4. Steel Z et al (2014) The global prevalence of common mental disorders: a systematic review and meta-analysis 1980–2013. Int J Epidemiol 43(2):476–493

    Article  PubMed  PubMed Central  Google Scholar 

  5. Fillingim RB et al (2013) Psychological factors associated with development of TMD: the OPPERA prospective cohort study. J Pain 14(12 Suppl):T75-90

    Article  PubMed  Google Scholar 

  6. Alles SRA, Smith PA (2018) Etiology and Pharmacology of Neuropathic Pain. Pharmacol Rev 70(2):315–347

    Article  CAS  PubMed  Google Scholar 

  7. West SJ et al (2015) Circuitry and plasticity of the dorsal horn–toward a better understanding of neuropathic pain. Neuroscience 300:254–275

    Article  CAS  PubMed  Google Scholar 

  8. Costigan M, Scholz J, Woolf CJ (2009) Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 32:1–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gracely RH, Lynch SA, Bennett GJ (1992) Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain 51(2):175–194

    Article  PubMed  Google Scholar 

  10. Zhou C, Luo ZD (2015) Nerve injury-induced calcium channel alpha-2-delta-1 protein dysregulation leads to increased pre-synaptic excitatory input into deep dorsal horn neurons and neuropathic allodynia. Eur J Pain 19(9):1267–1276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lai CY et al (2016) Spinal Fbxo3-Dependent Fbxl2 Ubiquitination of Active Zone Protein RIM1alpha Mediates Neuropathic Allodynia through CaV2.2 Activation. J Neurosci 36(37):9722–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Basbaum AI, Fields HL (1978) Endogenous pain control mechanisms: review and hypothesis. Ann Neurol 4(5):451–462

    Article  CAS  PubMed  Google Scholar 

  13. Lau BK, Vaughan CW (2014) Descending modulation of pain: the GABA disinhibition hypothesis of analgesia. Curr Opin Neurobiol 29:159–164

    Article  CAS  PubMed  Google Scholar 

  14. Heinricher MM et al (2009) Descending control of nociception: Specificity, recruitment and plasticity. Brain Res Rev 60(1):214–225

    Article  CAS  PubMed  Google Scholar 

  15. Geisler S et al (2007) Glutamatergic afferents of the ventral tegmental area in the rat. J Neurosci 27(21):5730–5743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ho YC, Cheng JK, Chiou LC (2013) Hypofunction of glutamatergic neurotransmission in the periaqueductal gray contributes to nerve-injury-induced neuropathic pain. J Neurosci 33(18):7825–7836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ho YC, Cheng JK, Chiou LC (2015) Impairment of adenylyl cyclase-mediated glutamatergic synaptic plasticity in the periaqueductal grey in a rat model of neuropathic pain. J Physiol 593(13):2955–2973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chou D et al (2018) (2R,6R)-hydroxynorketamine rescues chronic stress-induced depression-like behavior through its actions in the midbrain periaqueductal gray. Neuropharmacology 139:1–12

    Article  CAS  PubMed  Google Scholar 

  19. Ho YC et al (2018) Periaqueductal Gray Glutamatergic Transmission Governs Chronic Stress-Induced Depression. Neuropsychopharmacology 43(2):302–312

    Article  CAS  PubMed  Google Scholar 

  20. Yang PS et al (2020) NMDA receptor partial agonist GLYX-13 alleviates chronic stress-induced depression-like behavior through enhancement of AMPA receptor function in the periaqueductal gray. Neuropharmacology 178:108269

    Article  CAS  PubMed  Google Scholar 

  21. Peng WH, Kan HW, Ho YC (2022) Periaqueductal gray is required for controlling chronic stress-induced depression-like behavior. Biochem Biophys Res Commun 593:28–34

    Article  CAS  PubMed  Google Scholar 

  22. Kan HW et al (2022) Rapid antidepressant-like effects of muscarinic receptor antagonists require BDNF-dependent signaling in the ventrolateral periaqueductal gray. Psychopharmacology (Berl) 239(12):3805–3818

    Article  CAS  PubMed  Google Scholar 

  23. Lee MT et al (2022) Neurobiology of Depression: Chronic Stress Alters the Glutamatergic System in the Brain-Focusing on AMPA Receptor. Biomedicines 10(5):1005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hylden JL, Wilcox GL (1980) Intrathecal morphine in mice: a new technique. Eur J Pharmacol 67(2–3):313–316

    Article  CAS  PubMed  Google Scholar 

  25. Chaplan SR et al (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63

    Article  CAS  PubMed  Google Scholar 

  26. Malkesman O et al (2010) The female urine sniffing test: a novel approach for assessing reward-seeking behavior in rodents. Biol Psychiatry 67(9):864–871

    Article  CAS  PubMed  Google Scholar 

  27. Hsieh MC et al (2018) Spinal TNF-alpha impedes Fbxo45-dependent Munc13-1 ubiquitination to mediate neuropathic allodynia in rats. Cell Death Dis 9(8):811

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ho YC et al (2011) Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition. J Neurosci 31(41):14600–14610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Faul F et al (2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39(2):175–191

    Article  PubMed  Google Scholar 

  30. Pan YZ, Li DP, Pan HL (2002) Inhibition of glutamatergic synaptic input to spinal lamina II(o) neurons by presynaptic alpha(2)-adrenergic receptors. J Neurophysiol 87(4):1938–1947

    Article  CAS  PubMed  Google Scholar 

  31. Todd AJ, McGill MM, Shehab SA (2000) Neurokinin 1 receptor expression by neurons in laminae I, III and IV of the rat spinal dorsal horn that project to the brainstem. Eur J Neurosci 12(2):689–700

    Article  CAS  PubMed  Google Scholar 

  32. Dworkin RH, Gitlin MJ (1991) Clinical aspects of depression in chronic pain patients. Clin J Pain 7(2):79–94

    Article  CAS  PubMed  Google Scholar 

  33. Dworkin RH et al (2007) Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132(3):237–251

    Article  CAS  PubMed  Google Scholar 

  34. Maione S et al (2006) Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors. J Pharmacol Exp Ther 316(3):969–982

    Article  CAS  PubMed  Google Scholar 

  35. Mahler SV, Aston-Jones G (2018) CNO Evil? Considerations for the Use of DREADDs in Behavioral Neuroscience. Neuropsychopharmacology 43(5):934–936

    Article  PubMed  PubMed Central  Google Scholar 

  36. Polter AM, Kauer JA (2014) Stress and VTA synapses: implications for addiction and depression. Eur J Neurosci 39(7):1179–1188

    Article  PubMed  PubMed Central  Google Scholar 

  37. Zhuo M (2018) Long-term cortical synaptic changes contribute to chronic pain and emotional disorders. Neurosci Lett 702:66–70

    Article  PubMed  Google Scholar 

  38. Barthas F et al (2015) The anterior cingulate cortex is a critical hub for pain-induced depression. Biol Psychiatry 77(3):236–245

    Article  PubMed  Google Scholar 

  39. Duric V, McCarson KE (2006) Persistent pain produces stress-like alterations in hippocampal neurogenesis and gene expression. J Pain 7(8):544–555

    Article  PubMed  Google Scholar 

  40. Bliss TV et al (2016) Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat Rev Neurosci 17(8):485–496

    Article  CAS  PubMed  Google Scholar 

  41. Zhuo M (2016) Neural Mechanisms Underlying Anxiety-Chronic Pain Interactions. Trends Neurosci 39(3):136–145

    Article  CAS  PubMed  Google Scholar 

  42. Zhuo M (2016) Contribution of synaptic plasticity in the insular cortex to chronic pain. Neuroscience 338:220–229

    Article  CAS  PubMed  Google Scholar 

  43. Fields H (2004) State-dependent opioid control of pain. Nat Rev Neurosci 5(7):565–575

    Article  CAS  PubMed  Google Scholar 

  44. Neugebauer V et al (2004) The amygdala and persistent pain. Neuroscientist 10(3):221–234

    Article  PubMed  Google Scholar 

  45. Lerman SF et al (2015) Longitudinal associations between depression, anxiety, pain, and pain-related disability in chronic pain patients. Psychosom Med 77(3):333–341

    Article  CAS  PubMed  Google Scholar 

  46. Knaster P et al (2012) Psychiatric disorders as assessed with SCID in chronic pain patients: the anxiety disorders precede the onset of pain. Gen Hosp Psychiatry 34(1):46–52

    Article  PubMed  Google Scholar 

  47. Waung MW et al (2019) A Midbrain Circuit that Mediates Headache Aversiveness in Rats. Cell Rep 28(11):2739-2747 e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Suckow SK et al (2013) Columnar distribution of catecholaminergic neurons in the ventrolateral periaqueductal gray and their relationship to efferent pathways. Synapse 67(2):94–108

    Article  CAS  PubMed  Google Scholar 

  49. LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184

    Article  CAS  PubMed  Google Scholar 

  50. Liu D et al (2020) Mesocortical BDNF signaling mediates antidepressive-like effects of lithium. Neuropsychopharmacology 45(9):1557–1566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chaudhury D et al (2013) Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493(7433):532–536

    Article  CAS  PubMed  Google Scholar 

  52. Ikeda H et al (2006) Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 312(5780):1659–1662

    Article  CAS  PubMed  Google Scholar 

  53. Chang CH, Grace AA (2014) Amygdala-ventral pallidum pathway decreases dopamine activity after chronic mild stress in rats. Biol Psychiatry 76(3):223–230

    Article  CAS  PubMed  Google Scholar 

  54. Tye KM et al (2013) Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493(7433):537–541

    Article  CAS  PubMed  Google Scholar 

  55. Abedpoor N, Taghian F, Hajibabaie F (2022) Cross Brain-Gut Analysis Highlighted Hub Genes and LncRNA Networks Differentially Modified During Leucine Consumption and Endurance Exercise in Mice with Depression-Like Behaviors. Mol Neurobiol 59(7):4106–4123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to acknowledge the technical support by the Basic Medical Core Laboratory, I-Shou University College of Medicine. The authors would like to thank SATU Joint Research Scheme organized by Presidents’ Forum of Southeast Asia and Taiwan Universities (SATU) for the collaborative enhancement.

Funding

This work was supported by the Ministry of Science and Technology, Taipei, Taiwan (MOST 110–2511-H-002–020-MY3 to W.-H.P.; MOST 110–2320-B-214–002 to H.-W.K.; MOST 109–2320-B-214–001 and MOST 111–2628-B-214 -001 -MY3 to C.-C.W; MOST 108–2320-B-214–011-MY3 and MOST 111–2320-B-214 -002 -MY3 to Y.-C.H.), Fundamental Research Grant Scheme, Ministry of Higher Education, Malaysia (FRGS/1/2021/SKK06/UCSI/02/4 and FRGS/1/2021/WAB13/UCSI/02/1 to M.T.L.) and UCSI University Research Excellence and Innovation Grant, Malaysia (REIG-FPS-2020/065 to M.T.L.).

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, UCSI University, 56000, Cheras, Kuala Lumpur, Malaysia

    Ming Tatt Lee

  2. Centre of Research for Mental Health and Wellbeing, UCSI University, 56000, Cheras, Kuala Lumpur, Malaysia

    Ming Tatt Lee

  3. School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, 82445, Taiwan, Republic of China

    Ming Tatt Lee, Cheng-Chun Wu, Deng-Wu Wang, Yu-Ning Teng & Yu-Cheng Ho

  4. School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung City, 82445, Taiwan, Republic of China

    Wei-Hao Peng & Hung-Wei Kan

  5. School of Medicine, National Tsing Hua University, Hsinchu, 300044, Taiwan, Republic of China

    Wei-Hao Peng

  6. Department of Psychiatry, E-Da Hospital, Kaohsiung City, 82445, Taiwan, Republic of China

    Deng-Wu Wang

  7. School of Medicine, College of Medicine, I-Shou University, No.8, Yida Rd., Yanchao District, Kaohsiung City, 82445, Taiwan

    Yu-Cheng Ho

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Contributions

MTL, WHP, and YCH designed the studies, performed experiments, analyzed data, and wrote the draft manuscript. CCW and HWK conducted some behavioral experiments. DWW and YNT were involved in the revision of the final manuscript. YCH conceptualized, supervised the project, and prepared the manuscript with the help of all authors.

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Correspondence to Yu-Cheng Ho.

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All animal experiments were approved by the Institutional Animal Care and Use Committee of College of Medicine, I-Shou University following ARRIVE guidelines.

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Lee, M.T., Peng, WH., Wu, CC. et al. Impaired Ventrolateral Periaqueductal Gray-Ventral Tegmental area Pathway Contributes to Chronic Pain-Induced Depression-Like Behavior in Mice. Mol Neurobiol 60, 5708–5724 (2023). https://doi.org/10.1007/s12035-023-03439-z

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