Abstract
The perception of pain involves the activation of the spinal pathway as well as the supra-spinal pathway, which targets brain regions involved in affective and cognitive processes. Pain and emotions have the capacity to influence each other reciprocally; negative emotions, such as depression and anxiety, increase the risk for chronic pain, which may lead to anxiety and depression. The amygdala is a key-player in the expression of emotions, receives direct nociceptive information from the parabrachial nucleus, and is densely innervated by noradrenergic brain centers. In recent years, the amygdala has attracted increasing interest for its role in pain perception and modulation. In this review, we will give a short overview of structures involved in the pain pathway, zoom in to afferent and efferent connections to and from the amygdala, with emphasis on the direct parabrachio-amygdaloid pathway and discuss the evidence for amygdala’s role in pain processing and modulation. In addition to the involvement of the amygdala in negative emotions during the perception of pain, this brain structure is also a target site for many neuromodulators to regulate the perception of pain. We will end this article with a short review on the effects of noradrenaline and its role in hypoalgesia and analgesia.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Lang PJ. The emotion probe. Studies of motivation and attention. Am Psychol, 1995, 50: 372–385
Wiech K, Tracey I. The influence of negative emotions on pain: behavioral effects and neural mechanisms. Neuroimage, 2009, 47: 987–994
Magni G, Moreschi C, Rigatti-Luchini S, Merskey H. Prospective study on the relationship between depressive symptoms and chronic musculoskeletal pain. Pain, 1994, 56: 289–297
Carroll LJ, Cassidy JD, Cote P. Depression as a risk factor for onset of an episode of troublesome neck and low back pain. Pain, 2004, 107: 134–139
Kashikar-Zuck S, Goldschneider KR, Powers SW, Vaught MH, Hershey AD. Depression and functional disability in chronic pediatric pain. Clin J Pain, 2001, 17: 341–349
Rhudy JL, Meagher MW. Fear and anxiety: divergent effects on human pain thresholds. Pain, 2000, 84: 65–75
Kavaliers M. Brief exposure to a natural predator, the short-tailed weasel, induces benzodiazepine-sensitive analgesia in white-footed mice. Physiol Behav, 1988, 43: 187–193
Butler RK, Finn DP. Stress-induced analgesia. Prog Neurobiol, 2009, 88: 184–202
van der Kolk BA, Greenberg MS, Orr SP, Pitman RK. Endogenous opioids, stress induced analgesia, and posttraumatic stress disorder. Psychopharmacol Bull, 1989, 25: 417–421
McCarty R. Age-related alterations in sympathetic-adrenal medullary responses to stress. Gerontology, 1986, 32: 172–183
Morilak DA, Barrera G, Echevarria DJ, Garcia AS, Hernandez A, Ma S, Petre CO. Role of brain norepinephrine in the behavioral response to stress. Prog Neuropsychopharmacol Biol Psychiatry, 2005, 29: 1214–1224
Yoshimura M, Furue H. Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord. J Pharmacol Sci, 2006, 101: 107–117
Reddy SV, Yaksh TL. Spinal noradrenergic terminal system mediates antinociception. Brain Res, 1980, 189: 391–401
Ortiz JP, Close LN, Heinricher MM, Selden NR. Alpha(2)-noradrenergic antagonist administration into the central nucleus of the amygdala blocks stress-induced hypoalgesia in awake behaving rats. Neurosci, 2008, 157: 223–228
Pertovaara A. The noradrenergic pain regulation system: a potential target for pain therapy. Eur J Pharmacol, 2013, 716: 2–7
Nilsson U. The anxiety- and pain-reducing effects of music interventions: a systematic review. AORN J, 2008, 87: 780–807
Morley S. Efficacy and effectiveness of cognitive behaviour therapy for chronic pain: progress and some challenges. Pain, 2011, 152: S99–106
Bushnell MC, Ceko M, Low LA. Cognitive and emotional control of pain and its disruption in chronic pain. Nat Rev Neurosci, 2013, 14: 502–511
Willis WD, Westlund KN. Neuroanatomy of the pain system and of the pathways that modulate pain. J Clin Neurophysiol, 1997, 14: 2–31
Millan MJ. Descending control of pain. Prog Neurobiol, 2002, 66: 355–474
Gauriau C, Bernard JF. Pain pathways and parabrachial circuits in the rat. Exp Physiol, 2002, 87: 251–258
Benarroch EE. Pain-autonomic interactions. Neurol Sci, 2006, 27 (Suppl 2): S130–133
Burstein R, Cliffer KD, Giesler GJ Jr. Cells of origin of the spinohypothalamic tract in the rat. J Comp Neurol, 1990, 291: 329–344
Loewy AD, Araujo JC, Kerr FW. Pupillodilator pathways in the brain stem of the cat: anatomical and electrophysiological identification of a central autonomic pathway. Brain Res, 1973, 60: 65–91
Purves D, Augustine GJ, Fitzpatrick D. The nociceptive components of the thalamus and cortex. In: Purves D, Augustine G J, Fitzpatrick D, Katz L C, LaMantia AS, McNamara J O, Williams S M, eds. Neuroscience. 2nd ed. Sunderland: Sinauer Associates, 2001
Bushnell M C, Duncan G H, Hofbauer R K, Ha B, Chen JI, Carrier B. Pain perception: is there a role for primary somatosensory cortex? Proc Natl Acad Sci USA, 1999, 96: 7705–7709
LeDoux J E, Ruggiero D A, Forest R, Stornetta R, Reis DJ. Topographic organization of convergent projections to the thalamus from the inferior colliculus and spinal cord in the rat. J Comp Neurol, 1987, 264: 123–146
Turner BH, Herkenham M. Thalamoamygdaloid projections in the rat: a test of the amygdala’s role in sensory processing. J Comp Neurol, 1991, 313: 295–325
Mayer DJ, Liebeskind JC. Pain reduction by focal electrical stimulation of the brain: an anatomical and behavioral analysis. Brain Res, 1974, 68: 73–93
Turner BH, Mishkin M, Knapp M. Organization of the amygdalopetal projections from modality-specific cortical association areas in the monkey. J Comp Neurol, 1980, 191: 515–543
McDonald AJ, Mascagni F. Immunohistochemical localization of the beta 2 and beta 3 subunits of the gabaa receptor in the basolateral amygdala of the rat and monkey. Neurosci, 1996, 75: 407–419
LeDoux JE, Farb C, Ruggiero DA. Topographic organization of neurons in the acoustic thalamus that project to the amygdala. J Neurosci, 1990, 10: 1043–1054
Pape HC, Pare D. Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear. Physiol Rev, 2010, 90: 419–463
Krettek JE, Price JL. A description of the amygdaloid complex in the rat and cat with observations on intra-amygdaloid axonal connections. J Comp Neurol, 1978, 178: 255–280
Sah P, Faber ES, Lopez De Armentia M, Power J. The amygdaloid complex: anatomy and physiology. Physiol Rev, 2003, 83: 803–834
Morilak DA, Cecchi M, Khoshbouei H. Interactions of norepinephrine and galanin in the central amygdala and lateral bed nucleus of the stria terminalis modulate the behavioral response to acute stress. Life Sci, 2003, 73: 715–726
Shi C, Davis M. Pain pathways involved in fear conditioning measured with fearpotentiated startle: lesion studies. J Neurosci, 1999, 19: 420–430
McDonald AJ, Mascagni F, Guo L. Projections of the medial and lateral prefrontal cortices to the amygdala: a phaseolus vulgaris leucoagglutinin study in the rat. Neurosci, 1996, 71: 55–75
Bernard JF, Besson JM. The spino(trigemino)pontoamygdaloid pathway: electrophysiological evidence for an involvement in pain processes. J Neurophysiol, 1990, 63: 473–490
Saper CB, Loewy AD. Efferent connections of the parabrachial nucleus in the rat. Brain Res, 1980, 197: 291–317
Slugg RM, Light AR. Spinal cord and trigeminal projections to the pontine parabrachial region in the rat as demonstrated with phaseolus vulgaris leucoagglutinin. J Comp Neurol, 1994, 339: 49–61
Bernard JF, Alden M, Besson JM. The organization of the efferent projections from the pontine parabrachial area to the amygdaloid complex: a phaseolus vulgaris leucoagglutinin (pha-l) study in the rat. J Comp Neurol, 1993, 329: 201–229
Sarhan M, Freund-Mercier MJ, Veinante P. Branching patterns of parabrachial neurons projecting to the central extended amgydala: single axonal reconstructions. J Comp Neurol, 2005, 491: 418–442
Jhamandas JH, Petrov T, Harris KH, Vu T, Krukoff TL. Parabrachial nucleus projection to the amygdala in the rat: electrophysiological and anatomical observations. Brain Res Bull, 1996, 39: 115–126
Bernard JF, Huang GF, Besson JM. The parabrachial area: electrophysiological evidence for an involvement in visceral nociceptive processes. J Neurophysiol, 1994, 71: 1646–1660
Bernard JF, Huang GF, Besson JM. Nucleus centralis of the amygdala and the globus pallidus ventralis: electrophysiological evidence for an involvement in pain processes. J Neurophysiol, 1992, 68: 551–569
Neugebauer V, Li W. Processing of nociceptive mechanical and thermal information in central amygdala neurons with knee-joint input. J Neurophysiol, 2002, 87: 103–112
Bingel U, Quante M, Knab R, Bromm B, Weiller C, Büchel C. Subcortical structures involved in pain processing: evidence from single-trial fMRI. Pain, 2002, 99: 313–321
LeDoux J E, Iwata J, Cicchetti P, Reis DJ. Different projections of the central amygdaloid nucleus mediate autonomic and behavioural correlates of conditioned fear. J Neurosci, 1988, 8: 2517–2529
Bourgeais L, Gauriau C, Bernard JF. Projections from the nociceptive area of the central nucleus of the amygdala to the forebrain: a pha-l study in the rat. Eur J Neurosci, 2001, 14: 229–255
Veening JG, Swanson LW, Sawchenko PE. The organization of projections from the central nucleus of the amygdala to brainstem sites involved in central autonomic regulation: a combined retrograde transport-immunohistochemical study. Brain Res, 1984, 303: 337–357
Rizvi TA, Ennis M, Behbehani MM, Shipley MT. Connections between the central nucleus of the amygdala and the midbrain periaqueductal gray: topography and reciprocity. J Comp Neurol, 1991, 303: 121–131
Helmstetter FJ, Tershner SA, Poore LH, Bellgowan PS. Antinociception following opioid stimulation of the basolateral amygdala is expressed through the periaqueductal gray and rostral ventromedial medulla. Brain Res, 1998, 779: 104–118
Behbehani MM. Functional characteristics of the midbrain periaqueductal gray. Prog Neurobiol, 1995, 46: 575–605
Neugebauer V, Li W, Bird G C, Han JS. The amygdala and persistent pain. Neuroscientist, 2004, 10: 221–234
Crown E D, King T E, Meagher M W, Grau JW. Shock-induced hyperalgesia: III. Role of the bed nucleus of the stria terminalis and amygdaloid nuclei. Behav Neurosci, 2000, 114: 561–573
Calvino B, Levesque G, Besson JM. Possible involvement of the amygdaloid complex in morphine analgesia as studied by electrolytic lesions in rats. Brain Res, 1982, 233: 221–226
Mena NB, Mathur R, Nayar U. Amygdalar involvement in pain. Indian J Physiol Pharmacol, 1995, 39: 339–346
Fox RJ, Sorenson CA. Bilateral lesions of the amygdala attenuate analgesia induced by diverse environmental challenges. Brain Res, 1994, 648: 215–221
Fallon JH, Koziell DA, Moore RY. Catecholamine innervation of the basal forebrain. II. Amygdala, suprarhinal cortex and entorhinal cortex. J Comp Neurol, 1978, 180: 509–532
Zardetto-Smith AM, Gray TS. Catecholamine and npy efferents from the ventrolateral medulla to the amygdala in the rat. Brain Res Bull, 1995, 38: 253–260
Tanaka T, Yokoo H, Mizoguchi K, Yoshida M, Tsuda A, Tanaka M. Noradrenaline release in the rat amygdala is increased by stress: studies with intracerebral microdialysis. Brain Res, 1991, 544: 174–176
Khoshbouei H, Cecchi M, Dove S, Javors M, Morilak DA. Behavioral reactivity to stress: amplification of stress-induced noradrenergic activation elicits a galanin-mediated anxiolytic effect in central amygdala. Pharmacol Biochem Behav, 2002, 71: 407–417
Nalepa I, Vetulani J, Borghi V, Kowalska M, Przewłocka B, Pavone F. Formalin hindpaw injection induces changes in the [3H]prazosin binding to alpha1-adrenoceptors in specific regions of the mouse brain and spinal cord. J Neural Transm, 2005, 112: 1309–1319
Acosta-Martinez M, Fiber JM, Brown RD, Etgen AM. Localization of alpha1b-adrenergic receptor in female rat brain regions involved in stress and neuroendocrine function. Neurochem Int, 1999, 35: 383–391
Talley E M, Rosin D L, Lee A, Guyenet PG, Lynch KR. Distribution of alpha 2a-adrenergic receptor-like immunoreactivity in the rat central nervous system. J Comp Neurol, 1996, 372: 111–134
Rosin D L, Talley E M, Lee A, Stornetta RL, Gaylinn BD, Guyenet PG, Lynch KR. Distribution of alpha 2c-adrenergic receptor-like immunoreactivity in the rat central nervous system. J Comp Neurol, 1996, 372: 135–165
Scheinin M, Lomasney JW, Hayden-Hixson DM, Schambra UB, Caron MG, Lefkowitz RJ, Fremeau RT Jr. Distribution of alpha 2-adrenergic receptor subtype gene expression in rat brain. Brain Res Mol Brain Res, 1994, 21: 133–149
Wanaka A, Kiyama H, Murakami T, Matsumoto M, Kamada T, Malbon CC, Tohyama M. Immunocytochemical localization of beta-adrenergic receptors in the rat brain. Brain Res, 1989, 485: 125–140
Zaldivar A, Krichmar JL. Interactions between the neuromodulatory systems and the amygdala: exploratory survey using the allen mouse brain atlas. Brain Struct Funct, 2013, 218: 1513–1530
Delaney AJ, Crane JW, Sah P. Noradrenaline modulates transmission at a central synapse by a presynaptic mechanism. Neuron, 2007, 56: 880–892
Boyd RE. Alpha2-adrenergic receptor agonists as analgesics. Curr Top Med Chem, 2001, 1: 193–197
Fendt M, Koch M, Schnitzler HU. Amygdaloid noradrenaline is involved in the sensitization of the acoustic startle response in rats. Pharmacol Biochem Behav, 1994, 48: 307–314
Ortiz JP, Heinricher MM, Selden NR. Noradrenergic agonist administration into the central nucleus of the amygdala increases the tail-flick latency in lightly anesthetized rats. Neurosci, 2007, 148: 737–743
Lopez de Armentia M, Sah P. Bidirectional synaptic plasticity at nociceptive afferents in the rat central amygdala. J Physiol, 2007, 581: 961–970
Sun JY, Wu LG. Fast kinetics of exocytosis revealed by simultaneous measurements of presynaptic capacitance and postsynaptic currents at a central synapse. Neuron, 2001, 30: 171–182
Schneggenburger R, Forsythe ID. The calyx of held. Cell Tissue Res, 2006, 326: 311–337
van Stegeren AH. The role of the noradrenergic system in emotional memory. Acta Psychol, 2008, 127: 532–541
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published with open access at springerlink.fh-diploma.de
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Strobel, C., Hunt, S., Sullivan, R. et al. Emotional regulation of pain: the role of noradrenaline in the amygdala. Sci. China Life Sci. 57, 384–390 (2014). https://doi.org/10.1007/s11427-014-4638-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-014-4638-x