Skip to main content

Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat

Abstract

Deep brain stimulation has been found to be effective in relieving intractable pain. The ventral tegmental area (VTA) plays a role not only in the reward process, but also in the modulation of nociception. Lesions of VTA result in increased pain thresholds and exacerbate pain in several pain models. It is hypothesized that direct activation of VTA will reduce pain experience. In this study, we investigated the effect of direct electrical stimulation of the VTA on mechanical, thermal and carrageenan-induced chemical nociceptive thresholds in Sprague–Dawley rats using our custom-designed wireless stimulator. We found that: (1) VTA stimulation itself did not show any change in mechanical or thermal threshold; and (2) the decreased mechanical and thermal thresholds induced by carrageenan injection in the hind paw contralateral to the stimulation site were significantly reversed by VTA stimulation. To further explore the underlying mechanism of VTA stimulation-induced analgesia, spinal cord dorsal horn neuronal responses to graded mechanical stimuli were recorded. VTA stimulation significantly inhibited dorsal horn neuronal activity in response to pressure and pinch from the paw, but not brush. This indicated that VTA stimulation may have exerted its analgesic effect via descending modulatory pain pathways, possibly through its connections with brain stem structures and cerebral cortex areas.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  • Altier N, Stewart J (1998) Dopamine receptor antagonists in the nucleus accumbens attenuate analgesia induced by ventral tegmental area substance P or morphine and by nucleus accumbens amphetamine. J Pharmacol Exp Ther 285:208–215

    CAS  PubMed  Google Scholar 

  • Ativanichayaphong T, He JW, Hagains CE et al (2008) A combined wireless neural stimulating and recording system for study of pain processing. J Neurosci Methods 170:25–34. doi:10.1016/j.jneumeth.2007.12.014

    Article  PubMed  Google Scholar 

  • Bartsch T, Pinsker MO, Rasche D et al (2008) Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase series. Cephalalgia 28:285–295. doi:10.1111/j.1468-2982.2007.01531.x

    CAS  Article  PubMed  Google Scholar 

  • Boccard SGJ, Pereira EAC, Moir L et al (2013) Long-term outcomes of deep brain stimulation for neuropathic pain. Neurosurgery 72:221–230. doi:10.1227/NEU.0b013e31827b97d6

    Article  PubMed  Google Scholar 

  • Boccard SGJ, Fitzgerald JJ, Pereira EAC et al (2014) Targeting the affective component of chronic pain: a case series of deep brain stimulation of the anterior cingulate cortex. Neurosurgery 74:628–635. doi:10.1227/NEU.0000000000000321

    Article  PubMed  Google Scholar 

  • Brischoux F, Chakraborty S, Brierley DI, Ungless MA (2009) Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. Proc Natl Acad Sci USA 106:4894–4899. doi:10.1073/pnas.0811507106

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Broggi G, Franzini A, Leone M, Bussone G (2007) Update on neurosurgical treatment of chronic trigeminal autonomic cephalalgias and atypical facial pain with deep brain stimulation of posterior hypothalamus: results and comments. Neurol Sci 28:138–145. doi:10.1007/s10072-007-0767-3

    Article  Google Scholar 

  • Dixon WJ (1980) Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol 20:441–462

    CAS  Article  PubMed  Google Scholar 

  • Farajidavar A, Hagains CE, Peng YB et al (2010) Recognition and inhibition of dorsal horn nociceptive signals within a closed-loop system. In: 2010 Annual International Conference of the IEEE Engineering in Medicine and Biology Society EMBC’10, pp 1535–1538. doi:10.1109/IEMBS.2010.5626830

  • Farajidavar A, Hagains CE, Peng YB, Chiao JC (2012) A closed loop feedback system for automatic detection and inhibition of mechano-nociceptive neural activity. IEEE Trans Neural Syst Rehabil Eng 20:478–487. doi:10.1109/TNSRE.2012.2197220

    Article  PubMed  Google Scholar 

  • Fields HL, Hjelmstad GO, Margolis EB, Nicola SM (2007) Ventral tegmental area neurons in learned appetitive behavior and positive reinforcement. Annu Rev Neurosci 30:289–316. doi:10.1146/annurev.neuro.30.051606.094341

    CAS  Article  PubMed  Google Scholar 

  • Gao X, Zhang Y, Wu G (2000) Effects of dopaminergic agents on carrageenan hyperalgesia in rats. Eur J Pharmacol 406:53–58

    CAS  Article  PubMed  Google Scholar 

  • Gol A (1967) Relief of pain by electrical stimulation of the septal area. J Neurol Sci 5:115–120

    CAS  Article  PubMed  Google Scholar 

  • Goodman SJ, Holcombe V (1976) Selective and prolonged analgesia in monkey resulting from brain stimulation. In: Bonica JJ, Albe-Fessard DG (eds) Advances in Pain Research and Therapy. Raven Press, New York, pp 495–502  

    Google Scholar 

  • Greenspan JD, Craft RM, LeResche L et al (2007) Studying sex and gender differences in pain and analgesia: a consensus report. Pain. doi:10.1016/j.pain.2007.10.014

    Google Scholar 

  • Hagains CE, He J-W, Chiao J-C, Peng YB (2011) Septal stimulation inhibits spinal cord dorsal horn neuronal activity. Brain Res 1382:189–197. doi:10.1016/j.brainres.2011.01.074

    CAS  Article  PubMed  Google Scholar 

  • Hamani C, Schwalb JM, Rezai AR et al (2006) Deep brain stimulation for chronic neuropathic pain: long-term outcome and the incidence of insertional effect. Pain 125:188–196. doi:10.1016/j.pain.2006.05.019

    Article  PubMed  Google Scholar 

  • Hargreaves K, Dubner R, Brown F et al (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88

    CAS  Article  PubMed  Google Scholar 

  • Heath RG, Mickle WA (1960) Evaluation of seven years’ experience with depth electrode studies in human patients. In: Ramey ER, O’Doherty DS (eds) Electrical Studies on the Unanesthetized Brain. P. B. Hoeber, New York, pp 214–247

    Google Scholar 

  • Heinricher MM, Tavares I, Leith JL, Lumb BM (2009) Descending control of nociception: specificity, recruitment and plasticity. Brain Res Rev 60:214–225. doi:10.1016/j.brainresrev.2008.12.009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  • Hipolito L, Wilson-Poe A, Campos-Jurado Y et al (2015) Inflammatory pain promotes increased opioid self-administration: role of dysregulated ventral tegmental area opioid receptors. J Neurosci 35:12217–12231. doi:10.1523/JNEUROSCI.1053-15.2015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Hosobuchi Y (1980) The current status of analgesic brain stimulation. Acta Neurochir Suppl (Wien) 30:219–227

    CAS  Article  Google Scholar 

  • Hosobuchi Y, Adams JE, Rutkin B (1973) Chronic thalamic stimulation for the control of facial anesthesia dolorosa. Arch Neurol 29:158–161. doi:10.1001/archneur.1973.00490270040005

    CAS  Article  PubMed  Google Scholar 

  • Kender RG, Harte SE, Munn EM, Borszcz GS (2008) Affective analgesia following muscarinic activation of the ventral tegmental area in rats. J Pain 9:597–605. doi:10.1016/j.jpain.2008.01.334

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13:177–184

    CAS  Article  PubMed  Google Scholar 

  • Leknes S, Tracey I (2008) A common neurobiology for pain and pleasure. Nat Rev Neurosci 9:314–320. doi:10.1038/nrn2333

    CAS  Article  PubMed  Google Scholar 

  • Levy RM, Lamb S, Adams JE (1987) Treatment of chronic pain by deep brain stimulation: long term follow-up and review of the literature. Neurosurgery 21:885–893

    CAS  Article  PubMed  Google Scholar 

  • Li A, Wang Y, Yang X et al (2012) Stimulation of the ventral tegmental area inhibits spinal cord dorsal horn neuronal activity. In: Annual meeting of the Society for Neuroscience, New Orleans

  • Liebeskind JC, Guilbaud G, Besson JM, Oliveras JL (1973) Analgesia from electrical stimulation of the periaqueductal gray matter in the cat: behavioral observations and inhibitory effects on spinal cord interneurons. Brain Res 50:441–446. doi:10.1016/0006-8993(73)90748-8

    CAS  Article  PubMed  Google Scholar 

  • Ma QP, Zhou Y, Han JS (2000) Noxious stimulation accelerated the expression of c-fos protooncogene in cholecystokininergic and dopaminergic neurons in the ventral tegmental area. Peptides 14:561–566

    Article  Google Scholar 

  • Mallory GW, Abulseoud O, Hwang SC et al (2012) The nucleus accumbens as a potential target for central poststroke pain. Mayo Clin Proc 87:1025–1031. doi:10.1016/j.mayocp.2012.02.029

    Article  PubMed  PubMed Central  Google Scholar 

  • Margolis EB, Lock H, Hjelmstad GO, Fields HL (2006) The ventral tegmental area revisited: is there an electrophysiological marker for dopaminergic neurons? J Physiol 577:907–924. doi:10.1113/jphysiol.2006.117069

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Mayer DJ, Wolfle TL, Akil H et al (1971) Analgesia from electrical stimulation in the brainstem of the rat. Science 174:1351–1354

    CAS  Article  PubMed  Google Scholar 

  • Mazars G, Merienne L, Cioloca C (1974) Treatment of certain types of pain with implantable thalamic stimulators. Neurochirurgie 20:117–124

    CAS  PubMed  Google Scholar 

  • Messina G, Rizzi M, Cordella R et al (2012) Secondary chronic cluster headache treated by posterior hypothalamic deep brain stimulation: first reported case. Cephalgia 33:136–138. doi:10.1177/0333102412468675

    Article  Google Scholar 

  • Mogil JS, Chanda ML (2005) The case for the inclusion of female subjects in basic science studies of pain. Pain 117:1–5. doi:10.1016/j.pain.2005.06.020

    Article  PubMed  Google Scholar 

  • Moradi M, Fatahi Z, Haghparast A (2015a) Blockade of D1-like dopamine receptors within the ventral tegmental area and nucleus accumbens attenuates antinociceptive responses induced by chemical stimulation of the lateral hypothalamus. Neurosci Lett 599:61–66. doi:10.1016/j.neulet.2015.05.047

    CAS  Article  PubMed  Google Scholar 

  • Moradi M, Yazdanian M, Haghparast A (2015b) Role of dopamine D2-like receptors within the ventral tegmental area and nucleus accumbens in antinociception induced by lateral hypothalamus stimulation. Behav Brain Res 292:508–514. doi:10.1016/j.bbr.2015.07.007

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  • Morris CJ (2003) Carrageenan-induced paw edema in the rat and mouse. Methods Mol Biol 225:115–121. doi:10.1385/1-59259-374-7:115

    PubMed  Google Scholar 

  • Namburi P, Beyeler A, Yorozu S et al (2015) A circuit mechanism for differentiating positive and negative associations. Nature 520:675–678. doi:10.1038/nature14366

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Navratilova E, Xie JY, Okun A et al (2012) Pain relief produces negative reinforcement through activation of mesolimbic reward-valuation circuitry. Proc Natl Acad Sci USA 109:20709–20713. doi:10.1073/pnas.1214605109

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Neugebauer V, Li W, Bird GC, Han JS (2004) The amygdala and persistent pain. Neuroscientist 10:221–234. doi:10.1177/1073858403261077

    Article  PubMed  Google Scholar 

  • Oliveras JL, Besson JM, Guilbaud G, Liebeskind JC (1974) Behavioral and electrophysiological evidence of pain inhibition from midbrain stimulation in the cat. Exp Brain Res 20:32–44

    CAS  Article  PubMed  Google Scholar 

  • Oliveras JL, Redjemi F, Guilbaud G, Besson JM (1975) Analgesia induced by electrical stimulation of the inferior centralis nucleus of the raphe in the cat. Pain 1:139–145

    CAS  Article  PubMed  Google Scholar 

  • Paxinos G, Waston C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, San Diego

    Google Scholar 

  • Peng YB, Lin Q, Willis WD (1996a) The role of 5-HT3 receptors in periaqueductal gray-induced inhibition of nociceptive dorsal horn neurons in rats. J Pharmacol Exp Ther 276:116–124

    CAS  PubMed  Google Scholar 

  • Peng YB, Lin Q, Willis WD (1996b) Involvement of alpha-2 adrenoceptors in the periaqueductal gray-induced inhibition of dorsal horn cell activity in rats. J Pharmacol Exp Ther 278:125–135

    CAS  PubMed  Google Scholar 

  • Peng YB, Lin Q, Willis WD (1996c) Effects of GABA and glycine receptor antagonists on the activity and PAG-induced inhibition of rat dorsal horn neurons. Brain Res 736:189–201

    CAS  Article  PubMed  Google Scholar 

  • Peng YB, Lin Q, Willis WD (1997) Involvement of protein kinase C in responses of rat dorsal horn neurons to mechanical stimuli and periaqueductal gray descending inhibition. Exp Brain Res 114:561–570

    CAS  Article  PubMed  Google Scholar 

  • Rainov N, Heidecke V (2006) Motor cortex stimulation for neuropathic facial pain. Neurol Res 21:E6

    Google Scholar 

  • Rasche D, Rinaldi PC, Young RF, Tronnier VM (2006) Deep brain stimulation for the treatment of various chronic pain syndromes. Neurosurg Focus 21:E8. doi:10.3171/foc.2006.21.6.10

    PubMed  Google Scholar 

  • Reynolds DV (1969) Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 164:444–445

    CAS  Article  PubMed  Google Scholar 

  • Richardson DE, Akil H (1977a) Pain reduction by electrical brain stimulation in man. Part 2: chronic self-administration in the periventricular gray matter. J Neurosurg 47:184–194. doi:10.3171/jns.1977.47.2.0184

    CAS  Article  PubMed  Google Scholar 

  • Richardson DE, Akil H (1977b) Pain reduction by electrical brain stimulation in man. Part 1: acute administration in periaqueductal and periventricular sites. J Neurosurg 47:178–183

    CAS  Article  PubMed  Google Scholar 

  • Saadé NE, Atweh SF, Bahuth NB, Jabbur SJ (1997) Augmentation of nociceptive reflexes and chronic deafferentation pain by chemical lesions of either dopaminergic terminals or midbrain dopaminergic neurons. Brain Res 751:1–12

    Article  PubMed  Google Scholar 

  • Schifirnet E, Bowen SE, Borszcz GS (2014) Separating analgesia from reward within the ventral tegmental area. Neuroscience 263:72–87. doi:10.1016/j.neuroscience.2014.01.009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Schultz W (1997) A neural substrate of prediction and reward. Science 275:1593–1599. doi:10.1126/science.275.5306.1593

    CAS  Article  PubMed  Google Scholar 

  • Seijo F, Saiz A, Lozano B et al (2011) Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster headache: experience in five patients with a modified anatomical target. Cephalalgia 31:1634–1641. doi:10.1177/0333102411430264

    CAS  Article  PubMed  Google Scholar 

  • Senapati AK, Huntington PJ, LaGraize SC et al (2005a) Electrical stimulation of the primary somatosensory cortex inhibits spinal dorsal horn neuron activity. Brain Res 1057:134–140. doi:10.1016/j.brainres.2005.07.044

    CAS  Article  PubMed  Google Scholar 

  • Senapati AK, Huntington PJ, Peng YB (2005b) Spinal dorsal horn neuron response to mechanical stimuli is decreased by electrical stimulation of the primary motor cortex. Brain Res 1036:173–179. doi:10.1016/j.brainres.2004.12.043

    CAS  Article  PubMed  Google Scholar 

  • Senapati AK, Lagraize SC, Huntington PJ et al (2005c) Electrical Stimulation of the Anterior Cingulate Cortex Reduces Responses of Rat Dorsal Horn Neurons to Mechanical Stimuli. 94:845–851. doi:10.1152/jn.00040.2005

    Google Scholar 

  • Shipley MT, Ennis M, Rizvi TA, Behbehani MM (1991) The midbrain periaqueductal gray matter. Springer, Boston

    Google Scholar 

  • Sibi JE, Zuo C, Wang Y et al (2012) Stimulation of ventral tegmental area increases mechanical pain threshold and thermal pain latency in rats. In: Annual meeting of the Society for Neuroscience, New Orleans

  • Sotres-Bayón F, Torres-López E, López-Avila A et al (2001) Lesion and electrical stimulation of the ventral tegmental area modify persistent nociceptive behavior in the rat. Brain Res 898:342–349

    Article  PubMed  Google Scholar 

  • Spooner J, Yu H, Kao C et al (2007) Neuromodulation of the cingulum for neuropathic pain after spinal cord injury. Case report. J Neurosurg 107:169–172. doi:10.3171/JNS-07/07/0169

    Article  PubMed  Google Scholar 

  • Swanson LW (1982) The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull 9:321–353

    CAS  Article  PubMed  Google Scholar 

  • Takeda R, Ikeda T, Tsuda F et al (2005) Unilateral lesions of mesostriatal dopaminergic pathway alters the withdrawal response of the rat hindpaw to mechanical stimulation. Neurosci Res 52:31–36. doi:10.1016/j.neures.2005.01.005

    CAS  Article  PubMed  Google Scholar 

  • Taylor BK, Joshi C, Uppal H (2003) Stimulation of dopamine D2 receptors in the nucleus accumbens inhibits inflammatory pain. Brain Res 987:135–143

    CAS  Article  PubMed  Google Scholar 

  • Tsubokawa T, Katayama Y, Yamamoto T et al (1991) Chronic motor cortex stimulation for the treatment of central pain. Acta Neurochir Suppl (Wien) 52:137–139

    CAS  Article  Google Scholar 

  • Unruh AM (1996) Gender variations in clinical pain experience. Pain 65:123–167

    CAS  Article  PubMed  Google Scholar 

  • Waters AJ, Lumb BM (1997) Inhibitory effects evoked from both the lateral and ventrolateral periaqueductal grey are selective for the nociceptive responses of rat dorsal horn neurones. Brain Res 752:239–249. doi:10.1016/S0006-8993(96)01462-X

    CAS  Article  PubMed  Google Scholar 

  • Whalley K (2015) Neural circuits: pain or pleasure? Nat Rev Neurosci 16:316. doi:10.1038/nrn3975

    CAS  Article  PubMed  Google Scholar 

  • Wiech K, Kalisch R, Weiskopf N et al (2006) Anterolateral prefrontal cortex mediates the analgesic effect of expected and perceived control over pain. J Neurosci 26:11501–11509. doi:10.1523/JNEUROSCI.2568-06.2006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Wiesenfeldhallin Z (2005) Sex differences in pain perception. Gend Med 2:137–145. doi:10.1016/S1550-8579(05)80042-7

    Article  Google Scholar 

  • Winter CA, Risley EA, Nuss GW (1962) Carrageenin-induced edema in hind paw of the rat as an assay for antiinflammatory drugs. Proc Soc Exp Biol Med 111:544–547

    CAS  Article  PubMed  Google Scholar 

  • Wood PB (2006) Mesolimbic dopaminergic mechanisms and pain control. Pain 120:230–234. doi:10.1016/j.pain.2005.12.014

    CAS  Article  PubMed  Google Scholar 

  • Wood PB (2008) Role of central dopamine in pain and analgesia. Expert Rev Neurother 8:781–797. doi:10.1586/14737175.8.5.781

    CAS  Article  PubMed  Google Scholar 

  • Wood PB, Patterson JC, Sunderland JJ et al (2007) Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study. J Pain 8:51–58. doi:10.1016/j.jpain.2006.05.014

    CAS  Article  PubMed  Google Scholar 

  • Wood PB, Glabus MF, Simpson R, Patterson JC (2009) Changes in gray matter density in fibromyalgia: correlation with dopamine metabolism. J Pain 10:609–618. doi:10.1016/j.jpain.2008.12.008

    CAS  Article  PubMed  Google Scholar 

  • Young RF, Kroening R, Fulton W et al (1985) Electrical stimulation of the brain in treatment of chronic pain. J Neurosurg 62:389–396

    Article  PubMed  Google Scholar 

  • Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110

    CAS  Article  PubMed  Google Scholar 

  • Zuo C, Yang X, Wang Y et al (2012) A digital wireless system for closed-loop inhibition of nociceptive signals. J Neural Eng 9:056010. doi:10.1088/1741-2560/9/5/056010

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported in part by Texas Norman Hackerman Advanced Research Program (003656-0071-2009), Intel Corp, and TxMRC Grant. The authors wish to thank Dr. Amber L. Harris and Dr. Judith A. Strong who assisted in the proofreading of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yuan Bo Peng.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, AL., Sibi, J.E., Yang, X. et al. Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat. Exp Brain Res 234, 1505–1514 (2016). https://doi.org/10.1007/s00221-016-4558-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00221-016-4558-z

Keywords

  • Ventral tegmental area
  • Analgesia
  • Nociceptive threshold
  • Dorsal horn