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Differential associations between brain 5-HT1A receptor binding and response to pain versus touch

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Abstract

We studied whether brain serotonin 5-HT1A receptor availability is associated with response to noxious heat versus tactile stimuli, and short-term memory for heat pain. Psychophysical performance was assessed in 16 healthy subjects who had participated in a positron emission tomography study using [carbonyl-11C]WAY-100635 ligand for the assessment of 5-HT1A receptor binding potential (BP ND). Signal detection theory was applied to allow separate analysis of the subject’s sensory-discriminative capacity (sensory factor) and the attitude toward reporting a sensation (response criterion; non-sensory factor). Subject’s response criterion for heat pain was inversely correlated with 5-HT1A BP ND in the dorsal raphe, middle temporal gyrus, orbitofrontal cortex and posterior cingulum, whereas the subject’s discriminative capacity for touch was inversely correlated with 5-HT1A BP ND in the cingulum, inferior temporal gyrus, and medial prefrontal cortex. Certainty ratings of the responses, but not hit rates, in the pain memory task were correlated with 5-HT1A BP ND in the dorsal raphe.

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References

  • Albanese M-C, Duerden EG, Rainville P, Duncan GH (2007) Memory traces of pain in human cortex. J Neurosci 27:4612–4620

    Article  PubMed  CAS  Google Scholar 

  • Albert DJ, Walsh ML (1984) Neural systems and the inhibitory modulation of agonistic behavior: a comparison of mammalian species. Neurosci Biobehav Rev 8:5–24

    Article  PubMed  CAS  Google Scholar 

  • Artigas F, Romero L, de Montigny C, Blier P (1996) Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci 19:378–383

    Article  PubMed  CAS  Google Scholar 

  • Azmitia EC, Segal M (1978) An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. J Comp Neurol 179:641–668

    Article  PubMed  CAS  Google Scholar 

  • Borg J, Andrée B, Soderstrom H, Farde L (2003) The serotonin system and spiritual experiences. Am J Psychiatry 160:1965–1969

    Article  PubMed  Google Scholar 

  • Bromm B (2004) The involvement of the posterior cingulate gyrus in phasic pain processing in humans. Neurosci Lett 361:245–249

    Article  PubMed  CAS  Google Scholar 

  • Buhot M-C (1997) Serotonin receptors in cognitive behaviours. Curr Opin Neurobiol 7:243–254

    Article  PubMed  CAS  Google Scholar 

  • Bushnell MC, Apkarian AV (2006) Representation of pain in the brain. In: McMahon SB, Koltzenburg M (eds) Wall and Melzack’s textbook of pain, 5th edn. Elsevier, China, pp 107–124

    Google Scholar 

  • Carli M, Samanin R (2000) The 5-HT1A receptor agonist 8-OH-DPAT reduces rats’ accuracy of attentional performance and enhances impulsive responding in a five-choice serial reaction time task: role of presynaptic 5-HT1A receptors. Psychopharmacology (Berl) 149:259–268

    Article  CAS  Google Scholar 

  • Carli M, Balducci C, Samanin R (2000) Low doses of 8-OH-DPAT prevent the impairment of spatial learning caused by intrahippocampal scopolamine through 5-HT1A receptors in the dorsal raphe. Br J Pharmacol 131:375–381

    Article  PubMed  CAS  Google Scholar 

  • Casey KL, Tran TD (2006) Cortical mechanisms mediating acute and chronic pain in humans. In: Cervero F, Jensen TS (eds) Handbook of clinical neurology, vol 81. Elsevier, Amsterdam, pp 159–177

    Google Scholar 

  • Coghill RC, Sang CN, Maisog JM, Iadarola MJ (1999) Pain intensity processing within the human brain: a bilateral, distributed mechanism. J Neurophysiol 82:1934–1943

    PubMed  CAS  Google Scholar 

  • Colpaert FC (2006) 5-HT1A receptor activation: new molecular and neuroadaptive mechanisms of pain relief. Curr Opin Investig Drugs 7:40–47

    PubMed  CAS  Google Scholar 

  • Cooper JR, Bloom FE, Roth RH (2003) The biochemical basis of neuropharmacology. Oxford University Press, New York

    Google Scholar 

  • David SP, Murthy NV, Rabiner EA, Munafó MR, Johnstone EC, Jacob R, Walton RT, Grasby PM (2005) A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans. J Neurosci 25:2586–2590

    Article  PubMed  CAS  Google Scholar 

  • Devinsky O, Morrell MJ, Vogt BA (1995) Contributions of anterior cingulate cortex to behaviour. Brain 118:279–306

    Article  PubMed  Google Scholar 

  • Egashira N, Yano A, Ishigami N, Mishima K, Iwasaki K, Fujioka M, Matsushita M, Nishimura R, Fujiwara M (2006) Investigation of mechanisms mediating 8-OH-DPAT-induced impairment of spatial memory: involvement of 5-HT1A receptors in the dorsal hippocampus in rats. Brain Res 1069:54–62

    Article  PubMed  CAS  Google Scholar 

  • Fasmer OB, Berge OG, Post C, Hole K (1986) Effects of the putative 5-HT1A receptor agonist 8-OH-2-(di-n-propylamino)tetralin on nociceptive sensitivity in mice. Pharmacol Biochem Behav 25:883–888

    Article  PubMed  CAS  Google Scholar 

  • Friston KJ, Holmes AP, Worsley KJ, Poline JP, Frith C, Frackowiak RSJ (1995) Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 2:189–210

    Article  Google Scholar 

  • Gescheider GA (1997) Psychophysics. The fundamentals, 3rd edn. Lawrence Erlbaum Associates, Mahwah, pp 122–123

    Google Scholar 

  • Graeff FG, Guimarães FG, De Andrade TGCS, Deakin JFW (1996) Role of 5-HT in stress, anxiety and depression. Pharmacol Biochem Behav 54:129–141

    Article  PubMed  CAS  Google Scholar 

  • Hirvonen J, Kajander J, Allonen T, Oikonen V, Någren K, Hietala J (2007) Measurement of serotonin 5-HT1A receptor binding using positron emission tomography and [carbonyl-11C]WAY-100635—considerations on the validity of cerebellum as a reference region. J Cereb Blood Flow Metab 27:185–195

    Article  PubMed  CAS  Google Scholar 

  • Hirvonen J, Karlsson H, Kajander J, Lepola A, Markkula J, Rasi-Hakala H, Någren K, Salminen JK, Hietala J (2008) Decreased brain serotonin 5-HT1A receptor availability in medication-naïve patients with major depressive disorder: an in vivo imaging study using PET and [carbonyl-11C]WAY-100635. Int J Neuropsychopharmacol 11:465–476

    Article  PubMed  CAS  Google Scholar 

  • Hopwood SE, Stamford JA (2001) Multiple 5-HT1 receptor subtypes govern serotonin release in dorsal and median raphé nuclei. Neuropharmacology 40:508–519

    Article  PubMed  CAS  Google Scholar 

  • Hornung JP (2003) The human raphe nuclei and the serotonergic system. J Chem Neuroanat 26:331–343

    Article  PubMed  CAS  Google Scholar 

  • Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, Carson RE (2007) Concensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27:1533–1539

    Article  PubMed  CAS  Google Scholar 

  • Jovanovic H, Lundberg J, Karlsson P, Cerin A, Saijo T, Varrone A, Halldin C, Nordström AL (2008) Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET. NeuroImage 39:1408–1419

    Article  PubMed  Google Scholar 

  • Kayser V, Elfassi IE, Aubel B, Melfort M, Julius D, Gingrich JA, Hamon M, Bourgoin S (2007) Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A −/−, 5-HT1B −/−, 5-HT2A −/−, 5-HT3A −/− and 5-HTT −/− knock-out male mice. Pain 130:235–248

    Article  PubMed  CAS  Google Scholar 

  • Korneyev AY, Seredenin SB (1993) Effect of 5-HT-1A receptor agonists on paw licking reaction on hot plate and unpunished drinking in rat. Life Sci 52:997–1004

    Article  PubMed  CAS  Google Scholar 

  • Kulkarni D, Bentley DE, Elliott R, Youell P, Watson A, Derbyshire SWG, Frackowiak RSJ, Friston KJ, Jones AKP (2005) Attention to pain localization and unpleasantness discriminates the functions of the lateral and medial pain systems. Eur J Neurosci 21:3133–3142

    Article  PubMed  CAS  Google Scholar 

  • Lanzenberger RR, Mitterhauser M, Spindelegger C, Wadsak W, Klein N, Mien LK, Holik A, Attarbaschi T, Mossaheb N, Sacher J, Geiss-Granadia T, Kletter K, Kasper S, Tauscher J (2007) Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry 61:1081–1089

    Article  PubMed  CAS  Google Scholar 

  • Mann C, Croft RJ, Scholes KE, Dunne A, O’Neill BV, Leung S, Copolov D, Luan Phan K, Nathan PJ (2008) Differential effects of acute serotonin and dopamine depletion on prepulse inhibition and P50 suppression measures of sensorimotor and sensory gating in humans. Neuropsychopharmacology 33:1653–1666

    Article  PubMed  CAS  Google Scholar 

  • Martikainen IK, Hagelberg N, Mansikka H, Hietala J, Någren K, Scheinin H, Pertovaara A (2005) Association of dopamine D2/D3 receptor binding potential with pain but not tactile sensitivity or placebo analgesia. Neurosci Lett 376:149–156

    Article  PubMed  CAS  Google Scholar 

  • Martikainen IK, Hirvonen J, Kajander J, Hagelberg N, Mansikka H, Någren K, Hietala J, Pertovaara A (2007) Correlation of human cold pressor pain responses with 5-HT1A receptor binding in the brain. Brain Res 1172:21–31

    Article  PubMed  CAS  Google Scholar 

  • Meneses A, Perez-Garcia G (2007) 5-HT1A receptors and memory. Neurosci Biobehav Rev 31:705–727

    Article  PubMed  CAS  Google Scholar 

  • Mico JA, Berrocoso E, Ortega-Alvaro A, Gibert-Rahola J, Rojas-Corrales MO (2006) The role of 5-HT1A receptors in research strategy for extensive pain treatment. Curr Top Med Chem 6:1997–2003

    Article  PubMed  CAS  Google Scholar 

  • Miller EK, Cohen JD (2001) An integrative theory of prefrontal cortex function. Annu Rev Neurosci 24:167–202

    Article  PubMed  CAS  Google Scholar 

  • Oshiro Y, Quevedo AS, McHaffie JG, Kraft RA, Coghill RC (2007) Brain mechanisms supporting spatial discrimination of pain. J Neurosci 27:3388–3394

    Article  PubMed  CAS  Google Scholar 

  • Pache DM, Sewell RDE, Spencer PSJ (1999) Detecting drug effects on short-term memory function using a combined delayed matching and non-matching to position task. J Pharmacol Toxicol 41:135–141

    Article  CAS  Google Scholar 

  • Parsey RV, Arango V, Olvet DM, Oquendo MA, van Heertum RL, Mann JJ (2005) Regional heterogeneity of 5-HT1A receptors in human cerebellum as assessed by positron emission tomography. J Cereb Blood Flow Metab 25:785–793

    Article  PubMed  CAS  Google Scholar 

  • Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346:205–230

    Article  PubMed  CAS  Google Scholar 

  • Pertovaara A, Martikainen IK, Hagelberg N, Mansikka H, Någren K, Hietala J, Scheinin H (2004) Striatal dopamine D2/D3 receptor availability correlates with individual response characteristics to pain. Eur J Neurosci 20:1–6

    Article  Google Scholar 

  • Petrovic P, Petersson KM, Ghatan PH, Stone-Elander S, Ingvar M (2000) Pain-related cerebral activation is altered by a distracting cognitive task. Pain 85:19–30

    Article  PubMed  CAS  Google Scholar 

  • Pleger B, Ruff CC, Blankenburg F, Bestmann S, Wiech K, Stephan KE, Capilla A, Friston KJ, Dolan RJ (2006) Neural coding of tactile decisions in the human prefrontal cortex. J Neurosci 26:12596–12601

    Article  PubMed  CAS  Google Scholar 

  • Preuschhof C, Heekeren HR, Taskin B, Schubert T, Villringer A (2006) Neural correlates of vibrotactile working memory in the human brain. J Neurosci 26:13231–13239

    Article  PubMed  CAS  Google Scholar 

  • Quiton RL, Greenspan JD (2008) Across- and within-session variability of ratings of painful contact heat stimuli. Pain 137:245–256

    Article  PubMed  Google Scholar 

  • Rabiner EA, Messa C, Sargent PA, Husted-Kjaer K, Montgomery A, Lawrence AD, Bench CJ, Gunn RN, Cowen P, Grasby PM (2002) A database of [11C]WAY-100635 binding to 5-HT1A receptors in normal male volunteers: normative data and relationship to methodological, demographic, physiological, and behavioral variables. NeuroImage 15:620–632

    Article  PubMed  Google Scholar 

  • Rainville P, Doucet JC, Fortin MC, Duncan GH (2004) Rapid deterioration of pain sensory-discriminative information in short-term memory. Pain 110:605–615

    Article  PubMed  Google Scholar 

  • Romo R, Salinas E (2001) Touch and go: decision-making mechanisms in somatosensation. Annu Rev Neurosci 24:107–137

    Article  PubMed  CAS  Google Scholar 

  • Rosier EM, Iadarola MJ, Coghill RC (2002) Reproducibility of pain measurement and pain perception. Pain 98:205–216

    Article  PubMed  Google Scholar 

  • Ruotsalainen S, MacDonald E, Koivisto E, Stefanski R, Haapalinna A, Riekkinen P, JR Sirviö J (1998a) 5-HT1A receptor agonist (8-OH-DPAT) and 5-HT2 receptor agonist (DOI) disrupt the non-cognitive performance of rats in a working memory task. J Psychopharmacol 12:177–185

    Article  PubMed  CAS  Google Scholar 

  • Ruotsalainen S, Miettinen R, Macdonald E, Riekkinen M, Sirviö J (1998b) The role of the dorsal raphe-serotoninergic system and cholinergic receptors in the modulation of working memory. Neurosci Biobehav Rev 22:21–31

    Article  PubMed  CAS  Google Scholar 

  • Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, Gunn RN, Grasby PM, Cowen PJ (2000) Brain serotonin 1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 57:174–180

    Article  PubMed  CAS  Google Scholar 

  • Sommer C (2006) Is serotonin hyperalgesic or analgesic? Curr Pain Headache Rep 10:101–106

    Article  PubMed  Google Scholar 

  • Sotelo C, Cholley B, El Mestikawy S, Gozlan H, Hamon M (1990) Direct immunohistochemical evidence of the existence of 5-HT1A autoreceptors on serotonergic neurons in the midbrain raphe nuclei. Eur J Neurosci 2:1144–1154

    Article  PubMed  Google Scholar 

  • Swets JA (1973) The relative operating characteristic in psychology. Science 182:990–1000

    Article  PubMed  Google Scholar 

  • Tauscher J, Bagby RM, Javanmard M, Christensen BK, Kasper S, Kapur S (2001) Inverse relationship between serotonin 5-HT1A receptor binding and anxiety: A [11C]WAY-100635 PET investigation in healthy volunteers. Am J Psychiatry 158:1326–1328

    Article  PubMed  CAS  Google Scholar 

  • Wang Q-P, Nakai Y (1994) The dorsal raphe: an important nucleus in pain modulation. Brain Res Bull 34:575–585

    Article  PubMed  CAS  Google Scholar 

  • Warburton EC, Harrison AA, Robbins TW, Everitt BJ (1997) Contrasting effects of systemic and intracerebral infusions of the 5-HT1A receptor agonist 8-OH-DPAT on spatial short-term working memory in rats. Behav Brain Res 84:247–258

    Article  PubMed  CAS  Google Scholar 

  • Wei H, Pertovaara A (2006) 5-HT1A receptors in endogenous regulation of neuropathic hypersensitivity in the rat. Eur J Pharmacol 535:157–165

    Article  PubMed  CAS  Google Scholar 

  • Yamaguchi S, Knight RT (1990) Gating of somatosensory input by human prefrontal cortex. Brain Res 521:281–288

    Article  PubMed  CAS  Google Scholar 

  • Yasuno F, Suhara T, Nakayama T, Ichimiya T, Okubo Y, Takano A, Ando T, Inoue M, Maeda J, Suzuki K (2003) Inhibitory effect of hippocampal 5-HT1A receptors on human explicit memory. Am J Psychiatry 160:334–340

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was financially supported by the Research Programme on Neuroscience of the Academy of Finland and the Sigrid Jusélius Foundation, Helsinki, Finland. The staffs of Turku PET Centre and the MRI Unit of Turku University Hospital are acknowledged for skilful assistance in performing PET and MRI scanning.

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Authors and Affiliations

  1. Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland

    Ilkka K. Martikainen, Heikki Laurikainen, Heikki Tuikkala & Antti Pertovaara

  2. Department of Psychiatry, Turku University Hospital, Turku, Finland

    Jussi Hirvonen & Jarmo Hietala

  3. Turku PET Centre, University of Turku, Turku, Finland

    Jussi Hirvonen, Nora Hagelberg, Jaana Kajander, Kjell Någren & Jarmo Hietala

  4. Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland

    Ullamari Pesonen & Jaana Kajander

  5. Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital, Turku, Finland

    Nora Hagelberg

  6. Department of Physiology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland

    Antti Pertovaara

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  1. Ilkka K. Martikainen
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Correspondence to Ilkka K. Martikainen.

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Martikainen, I.K., Hirvonen, J., Pesonen, U. et al. Differential associations between brain 5-HT1A receptor binding and response to pain versus touch. J Neural Transm 116, 821–830 (2009). https://doi.org/10.1007/s00702-009-0248-3

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  • DOI: https://doi.org/10.1007/s00702-009-0248-3

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