, Volume 236, Issue 11, pp 3169–3182 | Cite as

Dopamine D1 and D2 receptors mediate analgesic and hypnotic effects of l-tetrahydropalmatine in a mouse neuropathic pain model

  • Yuan-Yuan Liu
  • Tian-Xiao Wang
  • Ji-Chuan Zhou
  • Wei-Min QuEmail author
  • Zhi-Li HuangEmail author
Original Investigation



Levo-tetrahydropalmatine (l-THP), an active ingredient of Corydalis yanhusuo, has been reported to be a partial agonist for dopamine D1 receptors (D1R) and an antagonist for D2R. Although it has been safely used clinically in China for decades as an analgesic with sedative/hypnotic properties, there are few studies that address the mechanisms by which l-THP exerts its beneficial effects in chronic pain-induced sleep disturbance.


To investigate the effects and mechanisms of l-THP on sleep disturbance in a neuropathic pain-like condition.


A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSNL) was employed. The antinociceptive and hypnotic effects of l-THP were evaluated by measurement of mechanical allodynia, thermal hyperalgesia, and electroencephalogram (EEG) recordings in PSNL mice. Pharmacological approaches and c-Fos expression were used to clarify the mechanisms of l-THP.


Intraperitoneal injection of l-THP at 5 and 10 mg/kg not only significantly increased the mechanical threshold by 134.4% and 174.8%, and prolonged the thermal latency by 49.4% and 69.2%, but also increased non-rapid eye movement sleep by 17.5% and 29.6%, and decreased sleep fragmentation in PSNL mice, compared with the vehicle control. Moreover, the antinociceptive effect of l-THP was prevented by D1R antagonist SCH23390 or D2R agonist quinpirole; meanwhile, the hypnotic effect of l-THP was blocked by quinpirole rather than by SCH23390. Immunohistochemistry demonstrated that l-THP inhibited c-Fos overexpression induced by PSNL in the cingulate cortex and the periaqueductal gray.


These findings indicated that l-THP exerted analgesic effects by agonism D1R and antagonism D2R, and the antagonism of D2R mediated the hypnotic effect of l-THP in PSNL mice.


Levo-tetrahydropalmatine Sleep disturbance Neuropathic pain Dopamine receptor c-Fos 



This manuscript is dedicated to the late Dr.Guo-Zhang Jin to acknowledge his many scientific contributions to dopamine studies. This work was supported in part by grants-in-aid for scientific research from the National Natural Science Foundation of China (Grant No. 31530035, 81420108015 to Zhi-Li Huang, Grant No. 31671099, 31871072 to Wei-Min Qu); the National Basic Research Program of China (Grant No. 2015CB856401 to Zhi-Li Huang); Program for Shanghai Outstanding Academic Leaders (to Zhi-Li Huang); and the Shanghai Committee of Science and Technology (Grant No. 17ZR1402000 to Yuan-Yuan Liu).

Compliance with ethical standards

Experimental protocols were approved by the Committee on the Ethics of Animal Experiments of Fudan University Shanghai Medical College and performed in accordance with ARRIVE  guidelines. Every effort was made to minimize the number of animals used and any pain or discomfort experienced by the mice.

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. Aira Z, Barrenetxea T, Buesa I, Garcia Del Cano G, Azkue JJ (2016) Dopamine D1-like receptors regulate constitutive, mu-opioid receptor-mediated repression of use-dependent synaptic plasticity in dorsal horn neurons: more harm than good? J Neurosci 36:5661–5673PubMedPubMedCentralGoogle Scholar
  2. Argoff CE (2007) The coexistence of neuropathic pain, sleep, and psychiatric disorders: a novel treatment approach. Clin J Pain 23:15–22PubMedGoogle Scholar
  3. Burgess CR, Tse G, Gillis L, Peever JH (2010) Dopaminergic regulation of sleep and cataplexy in a murine model of narcolepsy. Sleep 33:1295–1304PubMedPubMedCentralGoogle Scholar
  4. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63PubMedGoogle Scholar
  5. Cheatle MD, Foster S, Pinkett A, Lesneski M, Qu D, Dhingra L (2016) Assessing and managing sleep disturbance in patients with chronic pain. Anesthesiol Clin 34:379–393PubMedGoogle Scholar
  6. Chokroverty S (2000) Diagnosis and treatment of sleep disorders caused by co-morbid disease. Neurology 54:S8–S15PubMedGoogle Scholar
  7. Chu H, Jin G, Friedman E, Zhen X (2008) Recent development in studies of tetrahydroprotoberberines: mechanism in antinociception and drug addiction. Cell Mol Neurobiol 28:491–499PubMedGoogle Scholar
  8. Cobacho N, de la Calle JL, Paino CL (2014) Dopaminergic modulation of neuropathic pain: analgesia in rats by a D2-type receptor agonist. Brain Res Bull 106:62–71PubMedGoogle Scholar
  9. Dang YH, Xing B, Zhao Y, Zhao XJ, Huo FQ, Tang JS, Qu CL, Chen T (2011) The role of dopamine receptors in ventrolateral orbital cortex-evoked antinociception in a rat formalin test model. Eur J Pharmacol 657:97–103PubMedGoogle Scholar
  10. Devinsky O, Morrell MJ, Vogt BA (1995) Contributions of anterior cingulate cortex to behaviour. Brain 118 (Pt 1):279–306PubMedGoogle Scholar
  11. Dourado M, Cardoso-Cruz H, Monteiro C, Galhardo V (2016) Effect of motor impairment on analgesic efficacy of dopamine D2/3 receptors in a rat model of neuropathy. J Exp Neurosci 10:51–57PubMedPubMedCentralGoogle Scholar
  12. Ferini-Strambi L (2017) Neuropathic pain and sleep: a review. Pain Ther 6:19–23PubMedPubMedCentralGoogle Scholar
  13. Guo Z, Man Y, Wang X, Jin H, Sun X, Su X, Hao J, Mi W (2014) Levo-tetrahydropalmatine attenuates oxaliplatin-induced mechanical hyperalgesia in mice. Sci Rep 4:3905PubMedPubMedCentralGoogle Scholar
  14. Hsu B, Kin KC (1962) Pharmacological study of tetrahydropalmatine and its analogs. A new type of central depressants. Arch Int Pharmacodyn Ther 139:318–327PubMedGoogle Scholar
  15. Hu JY, Jin GZ (1999) Supraspinal D2 receptor involved in antinociception induced by l-tetrahydropalmatine. Zhongguo Yao Li Xue Bao 20:715–719PubMedGoogle Scholar
  16. Hu JY, Jin GZ (2000) Arcuate nucleus of hypothalamus involved in analgesic action of l-THP. Acta Pharmacol Sin 21:439–444PubMedGoogle Scholar
  17. Huang KX, Jin GZ (1992) The antagonistic effects of tetrahydroprotoberberines on dopamine receptors: electrophysiological studies. Sci China B 35:688–696PubMedGoogle Scholar
  18. Isaac SO, Berridge CW (2003) Wake-promoting actions of dopamine D1 and D2 receptor stimulation. J Pharmacol Exp Ther 307:386–394PubMedGoogle Scholar
  19. Jin GZ, Xu J, Zhang FT, Yu LP, Li JH, Wang XL (1983) Relevance of the sedative-tranquilizing effect of l-tetrahydropalmatine to brain monoaminergic neurotransmitters. Zhongguo Yao Li Xue Bao 4:4–10PubMedGoogle Scholar
  20. Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG, Group NCRRGW (2010) Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol 160:1577–1579PubMedPubMedCentralGoogle Scholar
  21. Kim JI, Ganesan S, Luo SX, Wu YW, Park E, Huang EJ, Chen L, Ding JB (2015) Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons. Science 350:102–106PubMedPubMedCentralGoogle Scholar
  22. Lazarus M, Chen JF, Urade Y, Huang ZL (2013) Role of the basal ganglia in the control of sleep and wakefulness. Curr Opin Neurobiol 23:780–785PubMedPubMedCentralGoogle Scholar
  23. Lazenka MF, Freitas KC, Henck S, Negus SS (2017) Relief of pain-depressed behavior in rats by activation of D1-like dopamine receptors. J Pharmacol Exp Ther 362:14–23PubMedPubMedCentralGoogle Scholar
  24. Liu YL, Liang JH, Yan LD, Su RB, Wu CF, Gong ZH (2005) Effects of l-tetrahydropalmatine on locomotor sensitization to oxycodone in mice. Acta Pharmacol Sin 26:533–538PubMedGoogle Scholar
  25. Liu YY, Yin D, Chen L, Qu WM, Chen CR, Laudon M, Cheng NN, Urade Y, Huang ZL (2014) Piromelatine exerts antinociceptive effect via melatonin, opioid, and 5HT1A receptors and hypnotic effect via melatonin receptors in a mouse model of neuropathic pain. Psychopharmacology 231:3973–3985PubMedGoogle Scholar
  26. Lu J, Jhou TC, Saper CB (2006) Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. J Neurosci 26:193–202PubMedPubMedCentralGoogle Scholar
  27. Luo YJ, Li YD, Wang L, Yang SR, Yuan XS, Wang J, Cherasse Y, Lazarus M, Chen JF, Qu WM, Huang ZL (2018) Nucleus accumbens controls wakefulness by a subpopulation of neurons expressing dopamine D1 receptors. Nat Commun 9:1576PubMedPubMedCentralGoogle Scholar
  28. Main DC, Waterman AE, Kilpatrick IC (1995) Behavioural analysis of changes in nociceptive thresholds produced by remoxipride in sheep and rats. Eur J Pharmacol 287:221–231PubMedGoogle Scholar
  29. Mansikka H, Erbs E, Borrelli E, Pertovaara A (2005) Influence of the dopamine D2 receptor knockout on pain-related behavior in the mouse. Brain Res 1052:82–87PubMedGoogle Scholar
  30. Meyer PJ, Morgan MM, Kozell LB, Ingram SL (2009) Contribution of dopamine receptors to periaqueductal gray-mediated antinociception. Psychopharmacology 204:531–540PubMedPubMedCentralGoogle Scholar
  31. Mo YQ, Jin XL, Chen YT, Jin GZ, Shi WX (2005) Effects of l-stepholidine on forebrain Fos expression: comparison with clozapine and haloperidol. Neuropsychopharmacology 30:261–267PubMedGoogle Scholar
  32. Monti JM, Monti D (2007) The involvement of dopamine in the modulation of sleep and waking. Sleep Med Rev 11:113–133PubMedGoogle Scholar
  33. Morin AK (2006) Strategies for treating chronic insomnia. Am J Manag Care 12:S230–S245PubMedGoogle Scholar
  34. Narita M, Niikura K, Nanjo-Niikura K, Furuya M, Yamashita A, Saeki M, Matsushima Y, Imai S, Shimizu T, Asato M, Kuzumaki N, Okutsu D, Miyoshi K, Suzuki M, Tsukiyama Y, Konno M, Yomiya K, Matoba M, Suzuki T (2011) Sleep disturbances in a neuropathic pain-like condition in the mouse are associated with altered GABAergic transmission in the cingulate cortex. Pain 152:1358–1372PubMedGoogle Scholar
  35. Narita M, Ozaki S, Ise Y, Yajima Y, Suzuki T (2003) Change in the expression of c-fos in the rat brain following sciatic nerve ligation. Neurosci Lett 352:231–233PubMedGoogle Scholar
  36. Ohtani N, Masaki E (2016) D2-like receptors in the descending dopaminergic pathway are not involved in the decreased postoperative nociceptive threshold induced by plantar incision in adult rats. J Pain Res 9:865–869PubMedPubMedCentralGoogle Scholar
  37. Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates. In: San Diego. Academic, Academic, San DiegoGoogle Scholar
  38. Qu WM, Huang ZL, Xu XH, Matsumoto N, Urade Y (2008) Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil. J Neurosci 28:8462–8469PubMedPubMedCentralGoogle Scholar
  39. Qu WM, Xu XH, Yan MM, Wang YQ, Urade Y, Huang ZL (2010) Essential role of dopamine D2 receptor in the maintenance of wakefulness, but not in homeostatic regulation of sleep, in mice. J Neurosci 30:4382–4389PubMedPubMedCentralGoogle Scholar
  40. Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC (1997) Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 277:968–971PubMedGoogle Scholar
  41. Rodella L, Rezzani R, Gioia M, Tredici G, Bianchi R (1998) Expression of Fos immunoreactivity in the rat supraspinal regions following noxious visceral stimulation. Brain Res Bull 47:357–366PubMedGoogle Scholar
  42. Sakai K (2018) Single unit activity of periaqueductal gray and deep mesencephalic nucleus neurons involved in sleep stage switching in the mouse. Eur J Neurosci 47:1110–1126PubMedGoogle Scholar
  43. Smith MT, Haythornthwaite JA (2004) How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature. Sleep Med Rev 8:119–132PubMedGoogle Scholar
  44. Takemura Y, Yamashita A, Horiuchi H, Furuya M, Yanase M, Niikura K, Imai S, Hatakeyama N, Kinoshita H, Tsukiyama Y, Senba E, Matoba M, Kuzumaki N, Yamazaki M, Suzuki T, Narita M (2011) Effects of gabapentin on brain hyperactivity related to pain and sleep disturbance under a neuropathic pain-like state using fMRI and brain wave analysis. Synapse 65:668–676PubMedGoogle Scholar
  45. Tuor UI, Malisza K, Foniok T, Papadimitropoulos R, Jarmasz M, Somorjai R, Kozlowski P (2000) Functional magnetic resonance imaging in rats subjected to intense electrical and noxious chemical stimulation of the forepaw. Pain 87:315–324PubMedGoogle Scholar
  46. Voulalas PJ, Ji Y, Jiang L, Asgar J, Ro JY, Masri R (2017) Loss of dopamine D1 receptors and diminished D1/5 receptor-mediated ERK phosphorylation in the periaqueductal gray after spinal cord lesion. Neuroscience 343:94–105PubMedGoogle Scholar
  47. Wang JB, Mantsch JR (2012) l-Tetrahydropalmatine: a potential new medication for the treatment of cocaine addiction. Future Med Chem 4:177–186PubMedGoogle Scholar
  48. Wang TX, Yin D, Guo W, Liu YY, Li YD, Qu WM, Han WJ, Hong ZY, Huang ZL (2015) Antinociceptive and hypnotic activities of pregabalin in a neuropathic pain-like model in mice. Pharmacol Biochem Behav 135:31–39PubMedGoogle Scholar
  49. Weizman T, Pick CG, Backer MM, Rigai T, Bloch M, Schreiber S (2003) The antinociceptive effect of amisulpride in mice is mediated through opioid mechanisms. Eur J Pharmacol 478:155–159PubMedGoogle Scholar
  50. Wood PB (2008) Role of central dopamine in pain and analgesia. Expert Rev Neurother 8:781–797PubMedGoogle Scholar
  51. Wu YE, Li YD, Luo YJ, Wang TX, Wang HJ, Chen SN, Qu WM, Huang ZL (2015) Gelsemine alleviates both neuropathic pain and sleep disturbance in partial sciatic nerve ligation mice. Acta Pharmacol Sin 36:1308–1317PubMedPubMedCentralGoogle Scholar
  52. Xu H, Wu LJ, Wang H, Zhang X, Vadakkan KI, Kim SS, Steenland HW, Zhuo M (2008) Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. J Neurosci 28:7445–7453PubMedPubMedCentralGoogle Scholar
  53. Xu Q, Xu XH, Qu WM, Lazarus M, Urade Y, Huang ZL (2014) A mouse model mimicking human first night effect for the evaluation of hypnotics. Pharmacol Biochem Behav 116:129–136PubMedGoogle Scholar
  54. Xu SX, Yu LP, Han YR, Chen Y, Jin GZ (1989) Effects of tetrahydroprotoberberines on dopamine receptor subtypes in brain. Zhongguo Yao Li Xue Bao 10:104–110PubMedGoogle Scholar
  55. Yamashita A, Hamada A, Suhara Y, Kawabe R, Yanase M, Kuzumaki N, Narita M, Matsui R, Okano H (2014) Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain. Synapse 68:235–247PubMedGoogle Scholar
  56. Yin D, Liu YY, Wang TX, Hu ZZ, Qu WM, Chen JF, Cheng NN, Huang ZL (2016) Paeoniflorin exerts analgesic and hypnotic effects via adenosine A1 receptors in a mouse neuropathic pain model. Psychopharmacology 233:281–293PubMedGoogle Scholar
  57. Zhang MQ, Wang TX, Li R, Huang ZL, Han WJ, Dai XC, Wang YQ (2017a) Helicid alleviates pain and sleep disturbances in a neuropathic pain-like model in mice. J Sleep Res 26:386–393PubMedGoogle Scholar
  58. Zhang Z, Wang HJ, Wang DR, Qu WM, Huang ZL (2017b) Red light at intensities above 10lx alters sleep-wake behavior in mice. Light Sci Appl 6:e16231PubMedPubMedCentralGoogle Scholar
  59. Zhou HH, Wu DL, Gao LY, Fang Y, Ge WH (2016) L-Tetrahydropalmatine alleviates mechanical hyperalgesia in models of chronic inflammatory and neuropathic pain in mice. Neuroreport 27:476–480PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, School of Basic Medical Sciences; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, and Institutes of Brain ScienceFudan UniversityShanghaiChina

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