Microinjection of valproic acid into the ventrolateral orbital cortex exerts an antinociceptive effect in a rat of neuropathic pain

Abstract

Rationale

Ventrolateral orbital cortex (VLO) has been found to play an important role in the regulation of neuropathic pain (NPP). As a traditional mood stabilizer, valproic acid (VPA) is currently employed in the treatment of NPP. However, whether VPA plays an analgesic role in VLO is still unknown.

Objectives

To elucidate the underlying analgesic mechanism of microinjection of VPA into the VLO on spared nerve injury (SNI), an animal model of NPP.

Methods

We firstly examined the role of VPA by intraperitoneal and intral-VLO injection. Then, we accessed its role as a histone deacetylase inhibitor by intral-VLO microinjection of sodium butyrate. Finally, the GABAergic mechanism was measured through the intra-VLO microinjection of several agonists and antagonists of various GABAergic receptor subtypes.

Results

Both intraperitoneal and intral-VLO injection of VPA attenuated SNI-induced mechanical allodynia. Microinjection of sodium butyrate, one of the histone deacetylase inhibitors, into the VLO attenuated the mechanical allodynia. Besides, microinjection of valpromide, a derivative of VPA which is a GABAergic agonist, into the VLO also attenuated allodynia. Furthermore, microinjection of picrotoxin, a GABAA receptor antagonist, into the VLO attenuated mechanical allodynia; microinjection of picrotoxin before VPA into the VLO increased VPA-induced anti-allodynia. Besides, microinjection of CGP 35348, a GABAB receptor antagonist, into the VLO attenuated allodynia; microinjection of CGP 35348 before VPA into the VLO also increased VPA-induced anti-allodynia. What is more, microinjection of imidazole-4-acetic acid (I4AA), a GABAC receptor antagonist, into the VLO enhanced allodynia; microinjection of I4AA before VPA into the VLO decreased VPA-induced anti-allodynia.

Conclusions

These results suggest that both the histone acetylation mechanism and GABAergic system are involved in mediating VLO-induced anti-hypersensitivity.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Bialer M (2012) Why are antiepileptic drugs used for nonepileptic conditions? Epilepsia 53(Suppl 7):26–33

    CAS  Article  Google Scholar 

  2. Bouhassira D (2019) Neuropathic pain: definition, assessment and epidemiology. Rev Neurol (Paris) 175:16–25

    CAS  Article  Google Scholar 

  3. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63

    CAS  Article  Google Scholar 

  4. Chebib M, Johnston GA (1999) The ‘ABC’ of GABA receptors: a brief review. Clin Exp Pharmacol Physiol 26:937–940

    CAS  Article  Google Scholar 

  5. Cincarova L, Zdrahal Z, Fajkus J (2013) New perspectives of valproic acid in clinical practice. Expert Opin Investig Drugs 22:1535–1547

    CAS  Article  Google Scholar 

  6. Cohen OS, Varlinskaya EI, Wilson CA, Glatt SJ, Mooney SM (2013) Acute prenatal exposure to a moderate dose of valproic acid increases social behavior and alters gene expression in rats. Int J Dev Neurosci 31:740–750

    CAS  Article  Google Scholar 

  7. Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A, Attal N, Finnerup NB, Eccleston C, Kalso E, Bennett DL, Dworkin RH, Raja SN (2017) Neuropathic pain. Nat Rev Dis Primers 3:17002

    Article  Google Scholar 

  8. Dang YH, Zhao Y, Xing B, Zhao XJ, Huo FQ, Tang JS, Qu CL, Chen T (2010) The role of dopamine receptors in ventrolateral orbital cortex-evoked anti-nociception in a rat model of neuropathic pain. Neuroscience 169:1872–1880

    CAS  Article  Google Scholar 

  9. Denk F, Huang W, Sidders B, Bithell A, Crow M, Grist J, Sharma S, Ziemek D, Rice AS, Buckley NJ, McMahon SB (2013) HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain. Pain 154:1668–1679

    CAS  Article  Google Scholar 

  10. Dufour-Rainfray D, Vourc'h P, Le Guisquet AM, Garreau L, Ternant D, Bodard S, Jaumain E, Gulhan Z, Belzung C, Andres CR, Chalon S, Guilloteau D (2010) Behavior and serotonergic disorders in rats exposed prenatally to valproate: a model for autism. Neurosci Lett 470:55–59

    CAS  Article  Google Scholar 

  11. Gill D, Derry S, Wiffen PJ, Moore RA (2011) Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev: CD009183

  12. Hardy JR, Rees EA, Gwilliam B, Ling J, Broadley K, A'Hern R (2001) A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain. J Pain Symptom Manag 21:204–209

    CAS  Article  Google Scholar 

  13. Huo FQ, Chen T, Lv BC, Wang J, Zhang T, Qu CL, Li YQ, Tang JS (2009) Synaptic connections between GABAergic elements and serotonergic terminals or projecting neurons in the ventrolateral orbital cortex. Cereb Cortex 19:1263–1272

    Article  Google Scholar 

  14. Huo FQ, Huang FS, Lv BC, Chen T, Feng J, Qu CL, Tang JS, Li YQ (2010) Activation of serotonin 1A receptors in ventrolateral orbital cortex depresses persistent nociception: a presynaptic inhibition mechanism. Neurochem Int 57:749–755

    CAS  Article  Google Scholar 

  15. Johnston GA, Chebib M, Hanrahan JR, Mewett KN (2010) Neurochemicals for the investigation of GABA(C) receptors. Neurochem Res 35:1970–1977

    CAS  Article  Google Scholar 

  16. Khangura RK, Bali A, Jaggi AS, Singh N (2017) Histone acetylation and histone deacetylation in neuropathic pain: an unresolved puzzle? Eur J Pharmacol 795:36–42

    CAS  Article  Google Scholar 

  17. Kukkar A, Singh N, Jaggi AS (2014) Attenuation of neuropathic pain by sodium butyrate in an experimental model of chronic constriction injury in rats. J Formos Med Assoc 113:921–928

    CAS  Article  Google Scholar 

  18. Lapane KL, Quilliam BJ, Benson C, Chow W, Kim MS (2015) Impact of noncancer pain on health-related quality of life. Pain Pract 15:333–342

    Article  Google Scholar 

  19. Lin H, Geng X, Dang W, Wu B, Dai Z, Li Y, Yang Y, Zhang H, Shi J (2012) Molecular mechanisms associated with the antidepressant effects of the class I histone deacetylase inhibitor MS-275 in the rat ventrolateral orbital cortex. Brain Res 1447:119–125

    CAS  Article  Google Scholar 

  20. Malcangio M (2018) GABAB receptors and pain. Neuropharmacology 136:102–105

    CAS  Article  Google Scholar 

  21. Qu CL, Tang JS, Jia H (2006) Involvement of GABAergic modulation of antinociception induced by morphine microinjected into the ventrolateral orbital cortex. Brain Res 1073-1074:281–289

    CAS  Article  Google Scholar 

  22. Reis GM, Duarte ID (2007) Involvement of chloride channel coupled GABA(C) receptors in the peripheral antinociceptive effect induced by GABA(C) receptor agonist cis-4-aminocrotonic acid. Life Sci 80:1268–1273

    CAS  Article  Google Scholar 

  23. Rosenberg G (2007) The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci 64:2090–2103

    CAS  Article  Google Scholar 

  24. Ross EL (2000) The evolving role of antiepileptic drugs in treating neuropathic pain. Neurology 55:S41–S46 discussion S54-8

    CAS  PubMed  Google Scholar 

  25. Shao Q, Li Y, Wang Q, Zhao J (2015) IL-10 and IL-1beta mediate neuropathic-pain like behavior in the ventrolateral orbital cortex. Neurochem Res 40:733–739

    CAS  Article  Google Scholar 

  26. Tadavarty R, Hwang J, Rajput PS, Soja PJ, Kumar U, Sastry BR (2015) Are presynaptic GABA-Crho2 receptors involved in anti-nociception? Neurosci Lett 606:145–150

    CAS  Article  Google Scholar 

  27. Tang JS, Qu CL, Huo FQ (2009) The thalamic nucleus submedius and ventrolateral orbital cortex are involved in nociceptive modulation: a novel pain modulation pathway. Prog Neurobiol 89:383–389

    Article  Google Scholar 

  28. Torrance N, Smith BH, Watson MC, Bennett MI (2007) Medication and treatment use in primary care patients with chronic pain of predominantly neuropathic origin. Fam Pract 24:481–485

    Article  Google Scholar 

  29. Wei L, Zhu YM, Zhang YX, Liang F, Barry DM, Gao HY, Li T, Huo FQ, Yan CX (2016a) Microinjection of histone deacetylase inhibitor into the ventrolateral orbital cortex potentiates morphine induced behavioral sensitization. Brain Res 1646:418–425

    CAS  Article  Google Scholar 

  30. Wei L, Zhu YM, Zhang YX, Liang F, Jia H, Qu CL, Wang J, Tang JS, Lu SM, Huo FQ, Yan CX (2016b) Activation of alpha1 adrenoceptors in ventrolateral orbital cortex attenuates allodynia induced by spared nerve injury in rats. Neurochem Int 99:85–93

    CAS  Article  Google Scholar 

  31. Xing B, Zhao Y, Zhang H, Dang Y, Chen T, Huang J, Luo Q (2011) Microinjection of valproic acid into the ventrolateral orbital cortex exerts an antidepressant-like effect in the rat forced swim test. Brain Res Bull 85:153–157

    CAS  Article  Google Scholar 

  32. Zhang S, Tang JS, Yuan B, Jia H (1998) Inhibitory effects of glutamate-induced activation of thalamic nucleus submedius are mediated by ventrolateral orbital cortex and periaqueductal gray in rats. Eur J Pain 2:153–163

    CAS  Article  Google Scholar 

Download references

Funding

This research was supported by the National Natural Science Foundation of China (NSFC No. 81771435 to Yong-hui Dang), the Natural Science Basic Research Plan in Shaanxi Province of China (No. 2016JM8078 to Yong-hui Dang), and the research project of State Key Laboratory for Manufacturing Systems Engineering (No. SKLMS 2017002).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yonghui Dang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chu, Z., Liu, P., Li, X. et al. Microinjection of valproic acid into the ventrolateral orbital cortex exerts an antinociceptive effect in a rat of neuropathic pain. Psychopharmacology (2020). https://doi.org/10.1007/s00213-020-05551-7

Download citation

Keywords

  • Ventrolateral orbital cortex
  • Neuropathic pain
  • Valproic acid
  • Histone deacetylase inhibitor
  • GABAergic modulation