The effect of opioid receptor blockade on the neural processing of thermal stimuli
Eszter D Schoell, Ulrike Bingel, Falk Eippert, Juliana Yacubian, Kerrin Christiansen, Hilke Andresen, Arne May, Christian Buechel, Eszter D Schoell, Ulrike Bingel, Falk Eippert, Juliana Yacubian, Kerrin Christiansen, Hilke Andresen, Arne May, Christian Buechel
Abstract
The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
References
- Bingel U, Tracey I. Imaging CNS modulation of pain in humans. Physiology (Bethesda) 2008;23:371–380.
- Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron. 2007;55:377–391.
- Benedetti F. Placebo and endogenous mechanisms of analgesia. Handb Exp Pharmacol. 2007. pp. 393–413.
- Willer JC, Dehen H, Cambier J. Stress-induced analgesia in humans: endogenous opioids and naloxone-reversible depression of pain reflexes. Science. 1981;212:689–691.
- Hebb ALO, Poulin J, Roach SP, Zacharko RM, Drolet G. Cholecystokinin and endogenous opioid peptides: interactive influence on pain, cognition, and emotion. Prog. Neuropsychopharmacol. Biol Psychiatry. 2005;29:1225–1238.
- Levine JD, Gordon NC, Jones RT, Fields HL. The narcotic antagonist naloxone enhances clinical pain. Nature. 1978;272:826–827.
- Davis KD, Wood ML, Crawley AP, Mikulis DJ. fMRI of human somatosensory and cingulate cortex during painful electrical nerve stimulation. Neuroreport. 1995;7:321–325.
- Peyron R, Laurent B, García-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin. 2000;30:263–288.
- Bingel U, Lorenz J, Schoell E, Weiller C, Büchel C. Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain. 2006;120:8–15.
- Eippert F, Bingel U, Schoell E, Yacubian J, Büchel C. Blockade of endogenous opioid neurotransmission enhances acquisition of conditioned fear in humans. J Neurosci. 2008;28:5465–5472.
- Lieberman MD, Jarcho JM, Berman S, Naliboff BD, Suyenobu BY, et al. The neural correlates of placebo effects: a disruption account. Neuroimage. 2004;22:447–455.
- Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia– imaging a shared neuronal network. Science. 2002;295:1737–1740.
- Rainville P, Hofbauer RK, Paus T, Duncan GH, Bushnell MC, et al. Cerebral mechanisms of hypnotic induction and suggestion. J Cogn Neurosci. 1999;11:110–125.
- Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science. 2004;303:1162–1167.
- Wiech K, Kalisch R, Weiskopf N, Pleger B, Stephan KE, et al. Anterolateral prefrontal cortex mediates the analgesic effect of expected and perceived control over pain. J Neurosci. 2006;26:11501–11509.
- Zubieta J, Bueller JA, Jackson LR, Scott DJ, Xu Y, et al. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci. 2005;25:7754–7762.
- Hill RG. The status of naloxone in the identification of pain control mechanisms operated by endogenous opioids. Neurosci Lett. 1981;21:217–222.
- Gutsein Howard B, Akil Huda. Opioid Analgesics. In: Brunton LL, Lazo JS, Parker K, editors. Goodman and Gilman's the Pharmacological Basis of Therapeutics. Mcgraw-Hill Higher Education; 2005. pp. 547–590.
- Mayberg H, Frost JJ. Opiate Receptors. In: Frost JJ, Wagner HNJM, editors. Quantitative Imaging: Neuroreceptors Neurotransmitters and Enzymes. New York, NY: Lippincott Williams and Wilkins.; 1990. pp. 81–95.
- Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci. 1999;19:484–494.
- Fruhstorfer H, Lindblom U, Schmidt WC. Method for quantitative estimation of thermal thresholds in patients. J Neurol Neurosurg Psychiatr. 1976;39:1071–1075.
- Bingel U, Schoell E, Herken W, Büchel C, May A. Habituation to painful stimulation involves the antinociceptive system. Pain. 2007;131:21–30.
- Wager TD, Scott DJ, Zubieta J. Placebo effects on human mu-opioid activity during pain. Proc Natl Acad Sci USA. 2007;104:11056–11061.
- Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage. 2002;15:273–289.
- El-Sobky A, Dostrovsky JO, Wall PD. Lack of effect of naloxone on pain perception in humans. Nature. 1976;263:783–784.
- Grevert P, Goldstein A. Endorphins: naloxone fails to alter experimental pain or mood in humans. Science. 1978;199:1093–1095.
- Posner J, Burke CA. The effects of naloxone on opiate and placebo analgesia in healthy volunteers. Psychopharmacology (Berl.) 1985;87:468–472.
- Kern D, Pelle-Lancien E, Luce V, Bouhassira D. Pharmacological dissection of the paradoxical pain induced by a thermal grill. Pain. 2008;135:291–299.
- Levine JD, Gordon NC. Influence of the method of drug administration on analgesic response. Nature. 1984;312:755–756.
- Levine JD, Gordon NC, Fields HL. Naloxone dose dependently produces analgesia and hyperalgesia in postoperative pain. Nature. 1979;278:740–741.
- Buchsbaum MS, Davis GC, Naber D, Pickar D. Pain enhances naloxone-induced hyperalgesia in humans as assessed by somatosensory evoked potentials. Psychopharmacology (Berl.) 1983;79:99–103.
- Anderson WS, Sheth RN, Bencherif B, Frost JJ, Campbell JN. Naloxone increases pain induced by topical capsaicin in healthy human volunteers. Pain. 2002;99:207–216.
- Koppert W, Angst M, Alsheimer M, Sittl R, Albrecht S, et al. Naloxone provokes similar pain facilitation as observed after short-term infusion of remifentanil in humans. Pain. 2003;106:91–99.
- Koppert W, Filitz J, Tröster A, Ihmsen H, Angst M, et al. Activation of naloxone-sensitive and -insensitive inhibitory systems in a human pain model. J Pain. 2005;6:757–764.
- Brennum J, Arendt-Nielsen L, Horn A, Secher NH, Jensen TS. Quantitative sensory examination during epidural anaesthesia and analgesia in man: effects of morphine. Pain. 1993;52:75–83.
- Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron. 2009;63:533–543.
- Borras MC, Becerra L, Ploghaus A, Gostic JM, DaSilva A, et al. fMRI measurement of CNS responses to naloxone infusion and subsequent mild noxious thermal stimuli in healthy volunteers. J Neurophysiol. 2004;91:2723–2733.
- Sprenger T, Valet M, Boecker H, Henriksen G, Spilker ME, et al. Opioidergic activation in the medial pain system after heat pain. Pain. 2006;122:63–67.
- Jones AK, Qi LY, Fujirawa T, Luthra SK, Ashburner J, et al. In vivo distribution of opioid receptors in man in relation to the cortical projections of the medial and lateral pain systems measured with positron emission tomography. Neurosci Lett. 1991;126:25–28.
- Sprenger T, Henriksen G, Valet M, Platzer S, Berthele A, et al. [Positron emission tomography in pain research. From the structure to the activity of the opiate receptor system]. Schmerz. 2007;21:503–513.
- Straube T, Schmidt S, Weiss T, Mentzel H, Miltner WH. Dynamic activation of the anterior cingulate cortex during anticipatory anxiety. NeuroImage. 2009;44:975–981.
- Britton KT, Southerland S. Naloxone blocks “anxiolytic” effects of neuropeptide Y. Peptides. 2001;22:607–612.
- Stacher G, Abatzi TA, Schulte F, Schneider C, Stacher-Janotta G, et al. Naloxone does not alter the perception of pain induced by electrical and thermal stimulation of the skin in healthy humans. Pain. 1988;34:271–276.
- Becerra L, Harter K, Gonzalez RG, Borsook D. Anesth. Analg 103: 208-216, table of contents; 2006. Functional magnetic resonance imaging measures of the effects of morphine on central nervous system circuitry in opioid-naive healthy volunteers.
- Millan MJ. Descending control of pain. Prog Neurobiol. 2002;66:355–474.
- Hao Y, Yang JY, Guo M, Wu CF, Wu MF. Morphine decreases extracellular levels of glutamate in the anterior cingulate cortex: an in vivo microdialysis study in freely moving rats. Brain Res. 2005;1040:191–196.
- Giacchino JL, Henriksen SJ. Opioid effects on activation of neurons in the medial prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry. 1998;22:1157–1178.
- Keith DE, Anton B, Murray SR, Zaki PA, Chu PC, et al. mu-Opioid receptor internalization: opiate drugs have differential effects on a conserved endocytic mechanism in vitro and in the mammalian brain. Mol Pharmacol. 1998;53:377–384.
- Carr DJ, Serou M. Exogenous and endogenous opioids as biological response modifiers. Immunopharmacology. 1995;31:59–71.
- Devor A, Tian P, Nishimura N, Teng IC, Hillman EMC, et al. Suppressed neuronal activity and concurrent arteriolar vasoconstriction may explain negative blood oxygenation level-dependent signal. J Neurosci. 2007;27:4452–4459.
- Shmuel A, Augath M, Oeltermann A, Logothetis NK. Negative functional MRI response correlates with decreases in neuronal activity in monkey visual area V1. Nat Neurosci. 2006;9:569–577.
- Standifer KM, Pasternak GW. G proteins and opioid receptor-mediated signalling. Cell Signal. 1997;9:237–248.
- Northoff G, Walter M, Schulte RF, Beck J, Dydak U, et al. GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI. Nat Neurosci. 2007;10:1515–1517.
- Haefely W. Pharmacology of benzodiazepine antagonists. Pharmacopsychiatry. 1985;18:163–166.
- Adler LJ, Gyulai FE, Diehl DJ, Mintun MA, Winter PM, et al. Regional brain activity changes associated with fentanyl analgesia elucidated by positron emission tomography. Anesth Analg. 1997;84:120–126.
- Casey KL, Svensson P, Morrow TJ, Raz J, Jone C, et al. Selective opiate modulation of nociceptive processing in the human brain. J Neurophysiol. 2000;84:525–533.
- Firestone LL, Gyulai F, Mintun M, Adler LJ, Urso K, et al. Human brain activity response to fentanyl imaged by positron emission tomography. Anesth Analg. 1996;82:1247–1251.
- Leppä M, Korvenoja A, Carlson S, Timonen P, Martinkauppi S, et al. Acute opioid effects on human brain as revealed by functional magnetic resonance imaging. Neuroimage. 2006;31:661–669.
- Wagner KJ, Sprenger T, Kochs EF, Tölle TR, Valet M, et al. Imaging human cerebral pain modulation by dose-dependent opioid analgesia: a positron emission tomography activation study using remifentanil. Anesthesiology. 2007;106:548–556.
- Wagner KJ, Willoch F, Kochs EF, Siessmeier T, Tölle TR, et al. Dose-dependent regional cerebral blood flow changes during remifentanil infusion in humans: a positron emission tomography study. Anesthesiology. 2001;94:732–739.
- Gläscher J. Visualization of group inference data in functional neuroimaging. Neuroinformatics. 2009;7:73–82.
Source: PubMed