Skip to main content

Advertisement

SpringerLink
Log in

Differential Roles of the D1- and D2-Like Dopamine Receptors Within the Ventral Tegmental Area in Modulating the Antinociception Induced by Forced Swim Stress in the Rat

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Several preclinical and clinical studies indicate that exposure to acute stress may decrease pain perception and increases pain tolerance. This phenomenon is called stress-induced analgesia (SIA). A variety of neurotransmitters, including dopamine, is involved in the SIA. Dopaminergic neurons in the mesolimbic circuits, originating from the ventral tegmental area (VTA), play a crucial role in various motivational, rewarding, and pain events. The present study aimed to investigate the modulatory role of VTA dopaminergic receptors in the antinociceptive responses evoked by forced swim stress (FSS) in a model of acute pain. One hundred-five adult male albino Wistar rats were subjected to stereotaxic surgery for implanting a unilateral cannula into the VTA. After one week of recovery, separate groups of animals were given different doses of SCH23390 and Sulpiride (0.25, 1, and 4 µg/0.3 µl) as D1- and D2-like receptor antagonists into the VTA, respectively. Then, the animals were exposed to FSS for a 6-min period, and the pain threshold was measured using the tail-flick test over a 60-min time set intervals. Results indicated that exposure to FSS produces a prominent antinociceptive response, diminishing by blocking both dopamine receptors in the VTA. Nonetheless, the effect of a D1-like dopamine receptor antagonist on FSS-induced analgesia was more prominent than that of a D2-like dopamine receptor antagonist. The results demonstrated that VTA dopaminergic receptors contribute to the pain process in stressful situations, and it might be provided a practical approach to designing new therapeutic agents for pain management.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

Data will be made available upon request. The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author at reasonable request.

References

  1. Świeboda P, Filip R, Prystupa A, Drozd M (2013) Assessment of pain: types, mechanism and treatment. Pain. ;2(7)

  2. Al Absi M, Rokke PD (1991) Can anxiety help us tolerate pain? Pain 46(1):43–51

    Article  PubMed  Google Scholar 

  3. Ferdousi M, Finn DP (2018) Stress-induced modulation of pain: role of the endogenous opioid system. Prog Brain Res 239:121–177

    Article  PubMed  Google Scholar 

  4. Janssen SA, Spinhoven P, Brosschot JF (2001) Experimentally induced anger, cardiovascular reactivity, and pain sensitivity. J Psychosom Res 51(3):479–485

    Article  PubMed  CAS  Google Scholar 

  5. Butler RK, Finn DP (2009) Stress-induced analgesia. Prog Neurobiol 88(3):184–202

    Article  PubMed  CAS  Google Scholar 

  6. Behbehani MM (1982) The role of acetylcholine in the function of the nucleus raphe magnus and in the interaction of this nucleus with the periaqueductal gray. Brain Res 252(2):299–307

    Article  PubMed  CAS  Google Scholar 

  7. Korzeniewska I, Płaźnik A (1995) Influence of serotonergic drugs on restraint stress induced analgesia. Pol J Pharmacol 47(5):381–385

    PubMed  CAS  Google Scholar 

  8. Strobel C, Hunt S, Sullivan R, Sun J, Sah P (2014) Emotional regulation of pain: the role of noradrenaline in the amygdala. Sci China Life Sci 57(4):384–390

    Article  PubMed  CAS  Google Scholar 

  9. Noursadeghi E, Haghparast A (2023) Modulatory role of intra-accumbal dopamine receptors in the restraint stress-induced antinociceptive responses. Brain Res Bull 195:172–179

    Article  PubMed  CAS  Google Scholar 

  10. Moteshakereh SM, Nikoohemmat M, Farmani D, Khosrowabadi E, Salehi S, Haghparast A (2023) The stress-induced antinociceptive responses to the persistent inflammatory pain involve the orexin receptors in the nucleus accumbens. Neuropeptides 98:102323

    Article  PubMed  CAS  Google Scholar 

  11. Cruz L, Basbaum AI (1985) Multiple opioid peptides and the modulation of pain: immunohistochemical analysis of dynorphin and enkephalin in the trigeminal nucleus caudalis and spinal cord of the cat. J Comp Neurol 240(4):331–348

    Article  PubMed  CAS  Google Scholar 

  12. Hatakeyama S, Kawai Y, Ueyama T, Senba E (1996) Nitric oxide synthase-containing magnocellular neurons of the rat hypothalamus synthesize oxytocin and vasopressin and express Fos following stress stimuli. J Chem Neuroanat 11(4):243–256

    Article  PubMed  CAS  Google Scholar 

  13. Mishra A, Singh S, Shukla S (2018) Physiological and functional basis of dopamine receptors and their role in neurogenesis: possible implication for Parkinson’s disease. J Exp Neurosci 12:1179069518779829

    Article  PubMed  PubMed Central  Google Scholar 

  14. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78(1):189–225

    Article  PubMed  CAS  Google Scholar 

  15. Bentivoglio M, Morelli M (2005) Chapter I the organization and circuits of mesencephalic dopaminergic neurons and the distribution of dopamine receptors in the brain. In: Dunnett SB, Bentivoglio M, Björklund A, Hökfelt T (eds) Handbook of Chemical Neuroanatomy, vol 21. Elsevier, pp 1–107

  16. Baik J-H (2020) Stress and the dopaminergic reward system. Exp Mol Med 52(12):1879–1890

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Bromberg-Martin ES, Matsumoto M, Hikosaka O (2010) Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68(5):815–834

    Article  PubMed Central  CAS  Google Scholar 

  18. Millan MJ (1999) The induction of pain: an integrative review. Prog Neurobiol 57(1):1–164

    Article  PubMed  CAS  Google Scholar 

  19. Abercrombie ED, Keefe KA, DiFrischia DS, Zigmond MJ (1989) Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex. J Neurochem 52(5):1655–1658

    Article  PubMed  CAS  Google Scholar 

  20. Anstrom KK, Woodward DJ (2005) Restraint increases dopaminergic burst firing in awake rats. Neuropsychopharmacology 30(10):1832–1840

    Article  PubMed  CAS  Google Scholar 

  21. Bassareo V, De Luca MA, Di Chiara G (2002) Differential expression of motivational stimulus properties by dopamine in nucleus accumbens shell versus core and prefrontal cortex. J Neurosci 22(11):4709–4719

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Brischoux F, Chakraborty S, Brierley DI, Ungless MA (2009) Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. Proceedings of the national academy of sciences. ;106(12):4894-9

  23. Dennis SG, Melzack R (1983) Effects of cholinergic and dopaminergic agents on pain and morphine analgesia measured by three pain tests. Exp Neurol 81(1):167–176

    Article  PubMed  CAS  Google Scholar 

  24. Morgan MJ, Franklin KB (1990) 6-Hydroxydopamine lesions of the ventral tegmentum abolishd-amphetamine and morphine analgesia in the formalin test but not in the tail flick test. Brain Res 519(1–2):144–149

    Article  PubMed  CAS  Google Scholar 

  25. Abdi Dezfouli R, Ghanbari Merdasi P, Rashvand M, Mousavi Z, Haghparast A (2022) The modulatory role of dopamine receptors within the hippocampal cornu ammonis area 1 in stress-induced analgesia in an animal model of persistent inflammatory pain. Behav Pharmacol 33(7):492–504

    Article  PubMed  CAS  Google Scholar 

  26. Merdasi PG, Dezfouli RA, Mazaheri S, Haghparast A (2022) Blocking the dopaminergic receptors in the hippocampal dentate gyrus reduced the stress-induced analgesia in persistent inflammatory pain in the rat. Physiol Behav 253:113848

    Article  PubMed  CAS  Google Scholar 

  27. Noursadeghi E, Rashvand M, Haghparast A (2022) Nucleus accumbens dopamine receptors mediate the stress-induced analgesia in an animal model of acute pain. Brain Res 1784:147887

    Article  PubMed  CAS  Google Scholar 

  28. Sanchez-Catalan MJ, Kaufling J, Georges F, Veinante P, Barrot M (2014) The antero-posterior heterogeneity of the ventral tegmental area. Neuroscience 282:198–216

    Article  PubMed  CAS  Google Scholar 

  29. Lammel S, Lim BK, Malenka RC (2014) Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 76:351–359

    Article  PubMed  CAS  Google Scholar 

  30. Brischoux F, Chakraborty S, Brierley DI, Ungless MA (2009) Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. Proc Natl Acad Sci U S A 106(12):4894–4899

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Hentall ID, Kim JL, Gollapudi L (1991) Responses of neurons in the ventromedial midbrain to noxious mechanical stimuli. Neurosci Lett 133(2):215–218

    Article  PubMed  CAS  Google Scholar 

  32. Martikainen IK (2009) Brain dopamine and serotonin receptors in the perception of pain. Positron emission tomography studies in healthy subjects Turun Yliopisto. University of Turku, Turku

    Google Scholar 

  33. D’Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72(1):74–79

    Google Scholar 

  34. Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates sixth edition by. Acad Press 170(547612):101016

    Google Scholar 

  35. Linthorst AC, Flachskamm C, Reul JM (2008) Water temperature determines neurochemical and behavioural responses to forced swim stress: an in vivo microdialysis and biotelemetry study in rats. Stress 11(2):88–100

    Article  PubMed  CAS  Google Scholar 

  36. Bannon AW, Malmberg AB (2007) Models of nociception: hot-plate, tail‐flick, and formalin tests in rodents. Curr Protoc Neurosci 41(1):8 1-8.9. 16

    Article  Google Scholar 

  37. Askari K, Oryan S, Eidi A, Zaringhalam J, Haghparast A (2023) Blockade of the orexin receptors in the ventral tegmental area could attenuate the stress-induced analgesia: a behavioral and molecular study. Prog Neuropsychopharmacol Biol Psychiatry 120:110639

    Article  PubMed  CAS  Google Scholar 

  38. Zareie F, Ghalebandi S, Askari K, Mousavi Z, Haghparast A (2022) Orexin receptors in the CA1 region of hippocampus modulate the stress-induced antinociceptive responses in an animal model of persistent inflammatory pain. Peptides 147:170679

    Article  PubMed  CAS  Google Scholar 

  39. Contet C, Gavériaux-Ruff C, Matifas A, Caradec C, Champy MF, Kieffer BL (2006) Dissociation of analgesic and hormonal responses to forced swim stress using opioid receptor knockout mice. Neuropsychopharmacology 31(8):1733–1744

    Article  PubMed  CAS  Google Scholar 

  40. Navratilova E, Porreca F (2014) Reward and motivation in pain and pain relief. Nat Neurosci 17(10):1304–1312

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Leknes S, Brooks JC, Wiech K, Tracey I (2008) Pain relief as an opponent process: a psychophysical investigation. Eur J Neurosci 28(4):794–801

    Article  PubMed  Google Scholar 

  42. Navratilova E, Xie JY, Okun A, Qu C, Eyde N, Ci S et al (2012) Pain relief produces negative reinforcement through activation of mesolimbic reward–valuation circuitry. Proceedings of the National Academy of Sciences. ;109(50):20709-13

  43. King T, Vera-Portocarrero L, Gutierrez T, Vanderah TW, Dussor G, Lai J et al (2009) Unmasking the tonic-aversive state in neuropathic pain. Nat Neurosci 12(11):1364–1366

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Wanigasekera V, Lee MC, Rogers R, Kong Y, Leknes S, Andersson J et al (2012) Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects. Proceedings of the National Academy of Sciences. ;109(43):17705-10

  45. Faramarzi G, Zendehdel M, Haghparast A (2016) 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 20(9):1423–1432

    Article  PubMed  CAS  Google Scholar 

  46. Albanese A, Minciacchi D (1983) Organization of the ascending projections from the ventral tegmental area: a multiple fluorescent retrograde tracer study in the rat. J Comp Neurol 216(4):406–420

    Article  PubMed  CAS  Google Scholar 

  47. Pignatelli M, Bonci A (2015) Role of dopamine neurons in reward and aversion: a synaptic plasticity perspective. Neuron 86(5):1145–1157

    Article  PubMed  CAS  Google Scholar 

  48. Hayes DJ, Chen DQ, Zhong J, Lin A, Behan B, Walker M et al (2017) Affective circuitry alterations in patients with trigeminal Neuralgia. Front Neuroanat 11:73

    Article  PubMed  PubMed Central  Google Scholar 

  49. Martikainen IK, Nuechterlein EB, Peciña M, Love TM, Cummiford CM, Green CR et al (2015) Chronic back Pain is Associated with alterations in dopamine neurotransmission in the ventral striatum. J Neurosci 35(27):9957–9965

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Potvin S, Grignon S, Marchand S (2009) Human evidence of a supra-spinal modulating role of dopamine on pain perception. Synapse 63(5):390–402

    Article  PubMed  CAS  Google Scholar 

  51. Holly EN, Miczek KA (2016) Ventral tegmental area dopamine revisited: effects of acute and repeated stress. Psychopharmacology 233(2):163–186

    Article  PubMed  CAS  Google Scholar 

  52. Watanabe M, Narita M, Hamada Y, Yamashita A, Tamura H, Ikegami D et al (2018) Activation of ventral tegmental area dopaminergic neurons reverses pathological allodynia resulting from nerve injury or bone cancer. Mol Pain 14:1744806918756406

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Sato D, Narita M, Hamada Y, Mori T, Tanaka K, Tamura H et al (2022) Relief of neuropathic pain by cell-specific manipulation of nucleus accumbens dopamine D1-and D2-receptor-expressing neurons. Mol Brain 15(1):1–13

    Google Scholar 

  54. Askari K, Oryan S, Eidi A, Zaringhalam J, Haghparast A (2021) Modulatory role of the orexin system in stress-induced analgesia: involvement of the ventral tegmental area. Eur J Pain 25(10):2266–2277

    Article  PubMed  CAS  Google Scholar 

  55. Fadel J, Deutch AY (2002) Anatomical substrates of orexin–dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111(2):379–387

    Article  PubMed  CAS  Google Scholar 

  56. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M et al (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435(1):6–25

    Article  PubMed  CAS  Google Scholar 

  57. Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE (2003) Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci 23(1):7–11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Safari-Sandiani E, Rahimitabar N, Rezaee L, Behnaz M, Haghparast A (2020) The contribution of orexin receptors within the ventral tegmental area to modulation of antinociception induced by chemical stimulation of the lateral hypothalamus in the animal model of orofacial pain in the rats. Behav Pharmacol 31(5):500–509

    Article  PubMed  CAS  Google Scholar 

  59. Matini T, Haghparast A, Rezaee L, Salehi S, Tehranchi A, Haghparast A (2020) Role of dopaminergic receptors within the ventral Tegmental Area in Antinociception Induced by Chemical Stimulation of the lateral hypothalamus in an animal model of Orofacial Pain. J Pain Res 13:1449–1460

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Ko MY, Jang EY, Lee JY, Kim SP, Whang SH, Lee BH et al (2018) The role of ventral Tegmental Area Gamma-Aminobutyric Acid in Chronic Neuropathic Pain after spinal cord Injury in rats. J Neurotrauma 35(15):1755–1764

    Article  PubMed  Google Scholar 

  61. Khaleghzadeh-Ahangar H, Rashvand M, Haghparast A (2021) Role of D1- and D2-like dopamine receptors within the dentate gyrus in antinociception induced by chemical stimulation of the lateral hypothalamus in an animal model of acute pain. Physiol Behav 229:113214

    Article  PubMed  CAS  Google Scholar 

  62. Shafiei I, Vatankhah M, Zarepour L, Ezzatpanah S, Haghparast A (2018) Role of D1- and D2-like dopaminergic receptors in the nucleus accumbens in modulation of formalin-induced orofacial pain: involvement of lateral hypothalamus. Physiol Behav 188:25–31

    Article  PubMed  CAS  Google Scholar 

  63. Siahposht-Khachaki A, Nazari-Serenjeh F, Rezaee L, Haghparast A, Rashvand M, Haghparast A (2021) Dopaminergic receptors in the ventral tegmental area modulated the lateral hypothalamic stimulation-induced antinociception in an animal model of tonic pain. Neurosci Lett 751:135827

    Article  PubMed  CAS  Google Scholar 

  64. Westerink B, Kwint H, DeVries J (1996) The pharmacology of mesolimbic dopamine neurons: a dual-probe microdialysis study in the ventral tegmental area and nucleus accumbens of the rat brain. J Neurosci 16(8):2605–2611

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Kavaliers M, Galea LAM (1995) Sex differences in the expression and antagonism of swim stress-induced analgesia in deer mice vary with the breeding season. Pain 63(3):327–334

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This project was supported by the Vice-Chancellor for Research & Technology of Shahid Beheshti University of Medical Sciences (No. 01-43003371-1401/09/05). Also, the authors would like to thank the Neurobiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences for cooperating in this work.

Funding

Funding for this study was provided by the Vice-Chancellor for Research & Technology of Shahid Beheshti University of Medical Sciences (No. 01-43003371-1401/09/05), Theran, Iran. The Vice-Chancellor for Research & Technology had no further role in the design of the study; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Author information

Authors and Affiliations

  1. Pharmacology and Toxicology Department, Faculty of Pharmacy and Pharmaceutical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

    Mohammad Saghafi & Zahra Mousavi

  2. Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, P.O.Box: 19615-1178, Tehran, Iran

    Elaheh Danesh, Reyhaneh Askari & Abbas Haghparast

  3. School of Cognitive Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran

    Abbas Haghparast

  4. Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran

    Abbas Haghparast

Authors
  1. Mohammad Saghafi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elaheh Danesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reyhaneh Askari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zahra Mousavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abbas Haghparast
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Abbas Haghparast was responsible for the study concept and design. Mohammad Saghafi and Elaheh Danesh acquired the behavioral data. Abbas Haghparast and Zahra Mousavi assisted with data analysis and interpretation of findings. Reyhaneh Askari and Mohammad Saghafi drafted the manuscript. Abbas Haghparast, Zahra Mousavi, and Reyhaneh Askari provided critical manuscript revision for important intellectual content. All authors critically reviewed the content and approved the final version for publication.

Corresponding author

Correspondence to Abbas Haghparast.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict 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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Saghafi, M., Danesh, E., Askari, R. et al. Differential Roles of the D1- and D2-Like Dopamine Receptors Within the Ventral Tegmental Area in Modulating the Antinociception Induced by Forced Swim Stress in the Rat. Neurochem Res 49, 143–156 (2024). https://doi.org/10.1007/s11064-023-04017-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-023-04017-4

Keywords

Search

Navigation