Original Report| Volume 16, ISSUE 5, P436-444, May 2015

Relationship Between Blood- and Cerebrospinal Fluid–Bound Neurotransmitter Concentrations and Conditioned Pain Modulation in Pain-Free and Chronic Pain Subjects

Published:February 04, 2015DOI:


      • Descending pain inhibition is deficient in chronic musculoskeletal pain subjects.
      • There was no change in cerebrospinal fluid monoamine levels in chronic pain subjects compared to controls.
      • Plasma norepinephrine and metanephrine levels decreased in chronic pain subjects versus controls.
      • Positive associations were found between plasma norepinephrine and metanephrine levels and conditioned pain modulation efficacy.


      Descending pain inhibition is an endogenous pain control system thought to depend partially on the activation of bulbospinal monoaminergic pathways. Deficits in descending pain inhibition have been reported in numerous human chronic pain conditions, but there is currently no consensus regarding the neurochemical correlates responsible for this deficit. The aims of this study were to 1) assess the efficacy of descending pain inhibition in pain-free and chronic pain subjects, 2) screen for changes in centrally (ie, cerebrospinal fluid) and peripherally (ie, plasma) acting monoamine concentrations, and 3) explore the relationship between descending pain inhibition and monoamine neurotransmitter concentrations. Our results clearly show a deficit in pain inhibition, along with lower plasma norepinephrine and metanephrine concentrations in chronic pain subjects, compared to pain-free subjects. No differences were found in cerebrospinal fluid neurotransmitter concentrations. Finally, our results revealed a positive relationship between blood-bound norepinephrine and metanephrine concentrations and the efficacy of descending pain inhibition. Thus, basal monoamine levels in blood were related to descending pain inhibition. This finding supports the emerging idea that individual differences in descending pain inhibition may be linked to individual differences in peripheral processes, such as monoamines release in blood, which are possibly related to cardiovascular control.


      This article presents psychophysical and neurochemical findings that indicate that the latent potential of descending pain inhibitory responses is associated with differential activity in peripheral processes governed by monoamine neurotransmitter release, bringing insights into the relationship between descending pain inhibition and cardiovascular control in humans.

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        • Beck A.T.
        • Ward C.H.
        • Mendelson M.
        • Mock J.
        • Erbaugh J.
        An inventory for measuring depression.
        Arch Gen Psychiatry. 1961; 4: 561-571
        • Berger M.
        • Gray J.A.
        • Roth B.L.
        The expanded biology of serotonin.
        Annu Rev Med. 2009; 60: 355-366
        • Bouwense S.A.W.
        • Olesen S.S.
        • Drewes A.M.
        • Poley J.-W.
        • van Goor H.
        • Wilder-Smith O.H.G.
        Effects of pregabalin on central sensitization in patients with chronic pancreatitis in a randomized, controlled trial.
        PLoS One. 2012; 7 (Eldabe S, editor): e42096
        • Brand T.
        • Anderson G.M.
        The measurement of platelet-poor plasma serotonin: A systematic review of prior reports and recommendations for improved analysis.
        Clin Chem. 2011; 57: 1376-1386
        • Chalaye P.
        • Devoize L.
        • Lafrenaye S.
        • Dallel R.
        • Marchand S.
        Cardiovascular influences on conditioned pain modulation.
        Pain. 2013; 154: 1377-1382
        • Chalaye P.
        • Goffaux P.
        • Bourgault P.
        • Lafrenaye S.
        • Devroede G.
        • Watier A.
        • Marchand S.
        Comparing pain modulation and autonomic responses in fibromyalgia and irritable bowel syndrome patients.
        Clin J Pain. 2012; 28: 519-526
        • Chalaye P.
        • Lafrenaye S.
        • Goffaux P.
        • Marchand S.
        The role of cardiovascular activity in fibromyalgia and conditioned pain modulation.
        Pain. 2014; 155: 1064-1069
        • Chorvatova A.
        • Couture R.
        Chapter 7: Pharmacologie du système nerveux autonome.
        in: Beaulieu P. Lambert C. Précis de pharmacologie: Du fondamental à la clinique. Montréal, Les Presses de l'Université de Montréal (PUM). 2010: 181-202
        • Cleeland C.S.
        • Ryan K.M.
        Pain assessment: Global use of the Brief Pain Inventory.
        Ann Acad Med Singapore. 1994; 23: 129-138
        • Daenen L.
        • Nijs J.
        • Roussel N.
        • Wouters K.
        • Loo M.
        • Cras P.
        Dysfunctional pain inhibition in patients with chronic whiplash-associated disorders: An experimental study.
        Clin Rheumatol. 2012; 32: 23-31
        • D’Andrea G.
        • D’Amico D.
        • Bussone G.
        • Bolner A.
        • Aguggia M.
        • Saracco M.G.
        • Galloni E.
        • De Riva V.
        • D’Arrigo A.
        • Colavito D.
        • Leon A.
        • Perini F.
        Tryptamine levels are low in plasma of chronic migraine and chronic tension-type headache.
        Neurol Sci. 2014; 35: 1941-1945
        • Edwards R.R.
        • Ness T.J.
        • Fillingim R.B.
        Endogenous opioids, blood pressure, and diffuse noxious inhibitory controls: A preliminary study.
        Percept Mot Skills. 2004; 99: 679-687
        • France R.D.
        • Urban B.J.
        • Pelton S.
        • Kilts C.D.
        • Hong J.S.
        • Nemeroff C.B.
        CSF monoamine metabolites in chronic pain.
        Pain. 1987; 31: 189-198
        • Ghia J.N.
        • Mueller R.A.
        • Duncan G.H.
        • Scott D.S.
        • Mao W.
        Serotonergic activity in man as a function of pain, pain mechanisms, and depression.
        Anesth Analg. 1981; 60: 854-861
        • Girard-Tremblay L.
        • Auclair V.
        • Daigle K.
        • Leonard G.
        • Whittingstall K.
        • Goffaux P.
        Sex differences in the neural representation of pain unpleasantness.
        J Pain. 2014; 15: 867-877
        • Guyenet P.G.
        The sympathetic control of blood pressure.
        Nat Rev Neurosci. 2006; 7: 335-346
        • Ji C.
        • Li W.
        • Ren X.-D.
        • El-Kattan A.F.
        • Kozak R.
        • Fountain S.
        • Lepsy C.
        Diethylation labeling combined with UPLC/MS/MS for simultaneous determination of a panel of monoamine neurotransmitters in rat prefrontal cortex microdialysates.
        Anal Chem. 2008; 80: 9195-9203
        • Kwon M.
        • Altin M.
        • Duenas H.
        • Alev L.
        The role of descending inhibitory pathways on chronic pain modulation and clinical implications.
        Pain Pract. 2013;
        • Legangneux E.
        • Mora J.J.
        • Spreux-Varoquaux O.
        • Thorin I.
        • Herrou M.
        • Alvado G.
        • Gomeni C.
        Cerebrospinal fluid biogenic amine metabolites, plasma-rich platelet serotonin and [3H]imipramine reuptake in the primary fibromyalgia syndrome.
        Rheumatology (Oxford). 2001; 40: 290-296
        • Marchand S.
        The physiology of pain mechanisms: From the periphery to the brain.
        Rheum Dis Clin North Am. 2008; 34: 285-309
        • Millan M.J.
        Descending control of pain.
        Prog Neurobiol. 2002; 66: 355-474
        • Ness T.J.
        • Lloyd L.K.
        • Fillingim R.B.
        An endogenous pain control system is altered in subjects with interstitial cystitis.
        J Urol. 2014; 191: 364-370
        • Niesters M.
        • Dahan A.
        • Swartjes M.
        • Noppers I.
        • Fillingim R.B.
        • Aarts L.
        • Sarton E.Y.
        Effect of ketamine on endogenous pain modulation in healthy volunteers.
        Pain International Association for the Study of Pain. 2011; 152: 656-663
        • Normand E.
        • Potvin S.
        • Gaumond I.
        • Cloutier G.
        • Corbin J.-F.
        • Marchand S.
        Pain inhibition is deficient in chronic widespread pain but normal in major depressive disorder.
        J Clin Psychiatry. 2011; 72: 219-224
        • Ossipov M.H.
        • Dussor G.O.
        • Porreca F.
        Central modulation of pain.
        J Clin Invest. 2010; 120: 3779-3787
        • Ossipov M.H.
        • Morimura K.
        • Porreca F.
        Descending pain modulation and chronification of pain.
        Curr Opin Support Palliat Care. 2014; 8: 143-151
        • Paul-Savoie E.
        • Marchand S.
        • Morin M.
        • Bourgault P.
        • Brissette N.
        • Rattanavong V.
        • Cloutier C.
        • Bissonnette A.
        • Potvin S.
        Is the deficit in pain inhibition in fibromyalgia influenced by sleep impairments?.
        Open Rheumatol J. 2012; 6: 296-302
        • Paul-Savoie E.
        • Potvin S.
        • Daigle K.
        • Normand E.
        • Corbin J.-F.
        • Gagnon R.
        • Marchand S.
        A deficit in peripheral serotonin levels in major depressive disorder but not in chronic widespread pain.
        Clin J Pain. 2011; 27: 529-534
        • Pertovaara A.
        Noradrenergic pain modulation.
        Prog Neurobiol. 2006; 80: 53-83
        • Pickering G.
        • Pereira B.
        • Dufour E.
        • Soule S.
        • Dubray C.
        Impaired modulation of pain in patients with postherpetic neuralgia.
        Pain Res Manag. 2014; 19: e19-e23
        • Pud D.
        • Granovsky Y.
        • Yarnitsky D.
        The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans.
        Pain. 2009; 144: 16-19
        • Shushan B.
        A review of clinical diagnostic applications of liquid chromatography-tandem mass spectrometry.
        Mass Spectrom Rev. 2010; 29: 930-944
        • Smits E.S.
        • Selles R.W.
        • Huygen F.J.P.
        • Duraku L.S.
        • Hovius S.E.R.
        • Walbeehm E.T.
        Disordered conditioned pain modulation system in patients with posttraumatic cold intolerance.
        J Plast Reconstr Aesthet Surg. 2014; 67: 68-73
        • Spielberger C.D.
        • Gorsuch R.L.
        • Lushene R.E.
        Manual for the State–Trait Anxiety.
        Consulting Psychologists Press, Palo Alto, CA1983
        • Staud R.
        Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions.
        Expert Rev Neurother. 2012; 12: 577-585
        • Strittmatter M.
        • Ostertag D.
        • Hoffmann K.H.
        • Paulus C.
        • Fischer C.
        • Meyer S.
        Monoaminergic transmitters in the cerebrospinal fluid of patients with acute, chronic, and intermittent pain. Interface between pain and depression?.
        Nervenarzt. 2005; 76: 443-452
        • Sullivan M.J.
        • Stanish W.
        • Waite H.
        • Sullivan M.
        • Tripp D.A.
        Catastrophizing, pain, and disability in patients with soft-tissue injuries.
        Pain. 1998; 77: 253-260
        • Task Force on Taxonomy of the International Association for the Study of Pain
        Merskey H. Bogduk N. Classification of Chronic Pain. 2nd ed. IASP Press, Seattle1994
        • Tousignant-Laflamme Y.
        • Pagé S.
        • Goffaux P.
        • Marchand S.
        An experimental model to measure excitatory and inhibitory pain mechanisms in humans.
        Brain Res. 2008; 1230: 73-79
        • Tousignant-Laflamme Y.
        • Rainville P.
        • Marchand S.
        Establishing a link between heart rate and pain in healthy subjects: A gender effect.
        J Pain. 2005; 6: 341-347
        • Tsigos C.
        • Reed P.
        • Weinkove C.
        • White A.
        • Young R.J.
        Plasma norepinephrine in sensory diabetic polyneuropathy.
        Diabetes Care. 1993; 16: 722-727
        • Watson C.P.N.
        • Gilron I.
        • Sawynok J.
        • Lynch M.E.
        Nontricyclic antidepressant analgesics and pain: Are serotonin norepinephrine reuptake inhibitors (SNRIs) any better?.
        Pain. 2011; 152: 2206-2210
        • Willer J.C.
        • Bouhassira D.
        • Le Bars D.
        Neurophysiological bases of the counterirritation phenomenon: diffuse control inhibitors induced by nociceptive stimulation.
        Neurophysiol Clin. 1999; 29: 379-400
        • Yarnitsky D.
        • Granot M.
        • Nahman-Averbuch H.
        • Khamaisi M.
        • Granovsky Y.
        Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.
        Pain. 2012; 153: 1193-1198
        • Yarnitsky D.
        Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): Its relevance for acute and chronic pain states.
        Curr Opin Anaesthesiol. 2010; 23: 611-615
        • Zamir N.
        • Maixner W.
        The relationship between cardiovascular and pain regulatory systems.
        Ann N Y Acad Sci. 1986; 467: 371-384