A parabrachial-to-amygdala circuit that determines hemispheric lateralization of somatosensory processing

Published:September 16, 2022DOI:



      The central amygdala (CeA) is a bilateral hub of pain and emotional processing with well-established functional lateralization. We reported that optogenetic manipulation of neural activity in the left and right CeA has opposing effects on bladder pain.


      To determine the influence of calcitonin gene-related peptide (CGRP) signaling from the parabrachial nucleus (PBN) on this diametrically opposed lateralization, we administered CGRP and evaluated the activity of CeA neurons in acute brain slices as well as the behavioral signs of bladder pain in the mouse.


      We found that CGRP increased firing in both the right and left CeA neurons. Furthermore, we found that CGRP administration in the right CeA increased behavioral signs of bladder pain and decreased bladder pain-like behavior when administered in the left CeA.


      These studies reveal a parabrachial-to-amygdala circuit driven by opposing actions of CGRP that determines hemispheric lateralization of visceral pain.


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      1. Ocklenburg S, Güntürkün O (2017): The Lateralized Brain: The Neuroscience and Evolution of Hemispheric Asymmetries. The Lateralized Brain: The Neuroscience and Evolution of Hemispheric Asymmetries. Elsevier Inc.

      2. Rogers LJ, Vallortigara G (2013): Divided Brains: The Biology and Behavior of Brain Asymmetries. Cambridge University Press.

        • Güntürkün O.
        • Ströckens F.
        • Ocklenburg S.
        Brain lateralization: A comparative perspective.
        Physiol Rev. 2020; 100: 1019-1063
        • Bach D.R.
        • Herdener M.
        • Grandjean D.
        • Sander D.
        • Seifritz E.
        • Strik W.K.
        Altered lateralisation of emotional prosody processing in schizophrenia.
        Schizophr Res. 2009; 110: 180-187
        • Taylor S.F.
        • Liberzon I.
        • Decker L.R.
        • Koeppe R.A.
        A functional anatomic study of emotion in schizophrenia.
        Schizophr Res. 2002;
        • Phan K.L.
        • Orlichenko A.
        • Boyd E.
        • Angstadt M.
        • Coccaro E.F.
        • Liberzon I.
        • Arfanakis K.
        Preliminary Evidence of White Matter Abnormality in the Uncinate Fasciculus in Generalized Social Anxiety Disorder.
        Biol Psychiatry. 2009; 66: 691-694
        • Hahn A.
        • Stein P.
        • Windischberger C.
        • Weissenbacher A.
        • Spindelegger C.
        • Moser E.
        • et al.
        Reduced resting-state functional connectivity between amygdala and orbitofrontal cortex in social anxiety disorder.
        Neuroimage. 2011;
        • Bruder G.E.
        • Stewart J.W.
        • Towey J.P.
        • Friedman D.
        • Tenke C.E.
        • Voglmaier M.M.
        • et al.
        Abnormal cerebral laterality in bipolar depression: Convergence of behavioral and brain event-related potential findings.
        Biol Psychiatry. 1992; 32: 33-47
        • Farahbod H.
        • Cook I.A.
        • Korb A.S.
        • Hunter A.M.
        • Leuchter A.F.
        Amygdala lateralization at rest and during viewing of neutral faces in major depressive disorder using low-resolution brain electromagnetic tomography.
        Clin EEG Neurosci. 2010; 41: 19-23
        • Frodl T.
        • Meisenzahl E.
        • Zetzsche T.
        • Bottlender R.
        • Born C.
        • Groll C.
        • et al.
        Enlargement of the amygdala in patients with a first episode of major depression.
        Biol Psychiatry. 2002; 51: 708-714
        • Rauch S.L.
        • Whalen P.J.
        • Shin L.M.
        • Mcinerney S.C.
        • Macklin M.L.
        • Lasko N.B.
        • et al.
        Exaggerated Amygdala Response to Masked Facial Stimuli in Posttraumatic Stress Disorder: A Functional MRI Study.
        Biological Psychiatry. 2000; 47: 769-776
        • Symonds L.L.
        • Gordon N.S.
        • Bixby J.C.
        • Mande M.M.
        Right-lateralized pain processing in the human cortex: An fMRI study.
        J Neurophysiol. 2006; 95: 3823-3830
      3. Allen HN, Bobnar HJ, Kolber BJ (2021, January 1): Left and right hemispheric lateralization of the amygdala in pain. Progress in Neurobiology, vol. 196. Elsevier Ltd.

      4. International Association for the Study of Pain (2003): How Prevalent is Chronic Pain? PAIN Clinical Updates XI.

        • Miller L.R.
        • Cano A.
        Comorbid Chronic Pain and Depression: Who Is at Risk?.
        Journal of Pain. 2009; 10: 619-627
      5. Schmidt-Wilcke T (2015, February 1): Neuroimaging of chronic pain. Best Practice and Research: Clinical Rheumatology, vol. 29. Bailliere Tindall Ltd, pp 29–41.

        • Simons L.E.
        • Moulton E.A.
        • Linnman C.
        • Carpino E.
        • Becerra L.
        • Borsook D.
        The human amygdala and pain: Evidence from neuroimaging.
        Hum Brain Mapp. 2014; 35: 527-538
        • Neugebauer V.
        • Li W.
        • Bird G.C.
        • Han J.S.
        The amygdala and persistent pain.
        Neuroscientist. 2004; 10: 221-234
        • Baas D.
        • Aleman A.
        • Kahn R.S.
        Lateralization of amygdala activation: A systematic review of functional neuroimaging studies.
        Brain Res Rev. 2004; 45: 96-103
        • Carrasquillo Y.
        • Gereau I.V.R.W.
        Hemispheric lateralization of a molecular signal for pain modulation in the amygdala.
        Mol Pain. 2008; 4
        • Ji G.
        • Neugebauer V.
        Hemispheric Lateralization of Pain Processing by Amygdala Neurons.
        J Neurophysiol. 2009; 102: 2253-2264
        • Wartolowska K.
        • Hough M.G.
        • Jenkinson M.
        • Andersson J.
        • Wordsworth B.P.
        • Tracey I.
        Structural changes of the brain in rheumatoid arthritis.
        Arthritis Rheum. 2012; 64: 371-379
        • Kulkarni B.
        • Bentley D.E.
        • Elliott R.
        • Youell P.
        • Watson A.
        • Derbyshire S.W.G.
        • et al.
        Attention to pain localization and unpleasantness discriminates the functions of the medial and lateral pain systems.
        European Journal of Neuroscience. 2005; 21: 3133-3142
        • Sadler K.E.
        • McQuaid N.A.
        • Cox A.C.
        • Behun M.N.
        • Trouten A.M.
        • Kolber B.J.
        Divergent functions of the left and right central amygdala in visceral nociception.
        Pain. 2017; 158: 747-759
        • Miyazawa Y.
        • Takahashi Y.
        • Watabe A.M.
        • Kato F.
        Predominant synaptic potentiation and activation in the right central amygdala are independent of bilateral parabrachial activation in the hemilateral trigeminal inflammatory pain model of rats.
        Mol Pain. 2018; 14
        • Kolber B.J.
        • Montana M.C.
        • Carrasquillo Y.
        • Xu J.
        • Heinemann S.F.
        • Muglia L.J.
        • Gereau R.W.
        Activation of Metabotropic Glutamate Receptor 5 in the Amygdala Modulates Pain-Like Behavior.
        Journal of Neuroscience. 2010; 30: 8203-8213
        • Carrasquillo Y.
        • Gereau R.W.
        Activation of the Extracellular Signal-Regulated Kinase in the Amygdala Modulates Pain Perception.
        Journal of Neuroscience. 2007; 27: 1543-1551
      6. Ikeda R, Takahashi Y, Inoue K, Kato F (2007): NMDA receptor-independent synaptic plasticity in the central amygdala in the rat model of neuropathic pain. Pain.

        • Cooper A.H.
        • Brightwell J.J.
        • Hedden N.S.
        • Taylor B.K.
        The left central nucleus of the amygdala contributes to mechanical allodynia and hyperalgesia following right-sided peripheral nerve injury.
        Neurosci Lett. 2018;
      7. Wall PD, Melzack R, Bonica JJ (1999): Textbook of Pain. Churchill Livingston Edinburgh.

        • Shoskes D.A.
        • Nickel J.C.
        • Rackley R.R.
        • Pontari M.A.
        Clinical phenotyping in chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis: A management strategy for urologic chronic pelvic pain syndromes.
        Prostate Cancer Prostatic Dis. 2009; 12: 177-183
      8. Adamian L, Urits I, Orhurhu V, Hoyt D, Driessen R, Freeman JA, et al. (2020, June 1): A Comprehensive Review of the Diagnosis, Treatment, and Management of Urologic Chronic Pelvic Pain Syndrome. Current Pain and Headache Reports, vol. 24. Springer.

      9. Zhang J, Liang CZ, Shang X, Li H (2020, January 1): Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Disease or Symptom? Current Perspectives on Diagnosis, Treatment, and Prognosis. American Journal of Men’s Health, vol. 14. SAGE Publications Inc.

        • Boezaart A.P.
        • Smith C.R.
        • Chembrovich S.
        • Zasimovich Y.
        • Server A.
        • Morgan G.
        • et al.
        Visceral versus somatic pain: an educational review of anatomy and clinical implications.
        Reg Anesth Pain Med. 2021; 46: 629-636
        • As-Sanie S.
        • Harris R.E.
        • Napadow V.
        • Kim J.
        • Neshewat G.
        • Kairys A.
        • et al.
        Changes in regional gray matter volume in women with chronic pelvic pain: A voxel-based morphometry study.
        Pain. 2012; 153: 1006-1014
        • Bagarinao E.
        • Johnson K.A.
        • Martucci K.T.
        • Ichesco E.
        • Farmer M.A.
        • Labus J.
        • et al.
        Preliminary structural MRI based brain classification of chronic pelvic pain: A MAPP network study.
        Pain. 2014; 155: 2502-2509
        • Kleinhans N.M.
        • Yang C.C.
        • Strachan E.D.
        • Buchwald D.S.
        • Maravilla K.R.
        Alterations in Connectivity on Functional Magnetic Resonance Imaging with Provocation of Lower Urinary Tract Symptoms: A MAPP Research Network Feasibility Study of Urological Chronic Pelvic Pain Syndromes.
        Journal of Urology. 2016; 195: 639-645
        • Nation K.M.
        • DeFelice M.
        • Hernandez P.I.
        • Dodick D.W.
        • Neugebauer V.
        • Navratilova E.
        • Porreca F.
        Lateralized Kappa Opioid Receptor Signaling from the Amygdala Central Nucleus Promotes Stress-Induced Functional Pain.
        Pain. 2018; 159: 1
        • Andreoli M.
        • Marketkar T.
        • Dimitrov E.
        Contribution of amygdala CRF neurons to chronic pain.
        Exp Neurol. 2017;
        • Wilson T.D.
        • Valdivia S.
        • Khan A.
        • Ahn H.-S.
        • Adke A.P.
        • Gonzalez S.M.
        • et al.
        Dual and Opposing Functions of the Central Amygdala in the Modulation of Pain.
        Cell Rep. 2019; 29 (e5): 332-346
        • Bourgeais L.
        • Gauriau C.
        • Bernard J.F.
        Projections from the nociceptive area of the central nucleus of the amygdala to the forebrain: A PHA-L study in the rat.
        European Journal of Neuroscience. 2001; 14: 229-255
        • Chiang M.C.
        • Bowen A.
        • Schier L.A.
        • Tupone D.
        • Uddin O.
        • Heinricher M.M.
        Parabrachial complex: A hub for pain and aversion.
        Journal of Neuroscience. 2019; 39: 8225-8230
      10. Sun L, Liu R, Guo F, Wen M qing, Ma X lin, Li K yuan, et al. (2020): Parabrachial nucleus circuit governs neuropathic pain-like behavior. Nat Commun 11.

        • Schwaber J.S.
        • Sternini C.
        • Brecha N.C.
        • Rogers W.T.
        • Card J.P.
        Neurons Containing Calcitonin Gene-Related Peptide in the Parabrachial Nucleus Project to the Central Nucleus of the Amygdala.
        Journal of Comparative Neurology. 1988; 270: 416-426
      11. Palmiter RD (2018, May 1): The Parabrachial Nucleus: CGRP Neurons Function as a General Alarm. Trends in Neurosciences, vol. 41. Elsevier Ltd, pp 280–293.

        • Boudes M.
        • Uvin P.
        • Kerselaers S.
        • Vennekens R.
        • Voets T.
        • De Ridder D.
        Functional characterization of a chronic cyclophosphamide-induced overactive bladder model in mice.
        Neurourol Urodyn. 2011; 30: 1659-1665
        • Stillwell T.J.
        • Benson R.C.
        Cyclophosphamide‐induced hemorrhagic cystitis: A review of 100 patients.
        Cancer. 1988; 61: 451-457
        • Sadler K.E.
        • Stratton J.M.
        • Kolber B.J.
        Urinary bladder distention evoked visceromotor responses as a model for bladder pain in mice.
        Journal of Visualized Experiments. 2014;
        • Tye K.M.
        • Prakash R.
        • Kim S.Y.
        • Fenno L.E.
        • Grosenick L.
        • Zarabi H.
        • et al.
        Amygdala circuitry mediating reversible and bidirectional control of anxiety.
        Nature. 2011; 471: 358-362
        • Chaplan S.R.
        • Bach F.W.
        • Pogrel J.W.
        • Chung J.M.
        • Yaksh T.L.
        Quantitative assessment of tactile allodynia in the rat paw.
        Journal of Neuroscience Methods. 1994; 53
        • Block C.H.
        • Hoffman G.
        • Kapp B.S.
        Peptide-containing pathways from the parabrachial complex to the central nucleus of the amygdala.
        Peptides. 1989; 10
        • Sugimura Y.K.
        • Takahashi Y.
        • Watabe A.M.
        • Kato F.
        Synaptic and network consequences of monosynaptic nociceptive inputs of parabrachial nucleus origin in the central amygdala.
        J Neurophysiol. 2016; 115: 2721-2739
        • Felix-Ortiz A.C.
        • Beyeler A.
        • Seo C.
        • Leppla C.A.
        • Wildes C.P.
        • Tye K.M.
        BLA to vHPC inputs modulate anxiety-related behaviors.
        Neuron. 2013; 79: 658-664
        • Kim J.
        • Zhang X.
        • Muralidhar S.
        • LeBlanc S.A.
        • Tonegawa S.
        Basolateral to Central Amygdala Neural Circuits for Appetitive Behaviors.
        Neuron. 2017; 93 (e5): 1464-1479
        • Shinohara K.
        • Watabe A.M.
        • Nagase M.
        • Okutsu Y.
        • Takahashi Y.
        • Kurihara H.
        • Kato F.
        Essential role of endogenous calcitonin gene-related peptide in pain-associated plasticity in the central amygdala.
        European Journal of Neuroscience. 2017;
        • Han J.S.
        • Li W.
        • Neugebauer V.
        Critical Role of Calcitonin Gene-Related Peptide 1 Receptors in the Amygdala in Synaptic Plasticity and Pain Behavior.
        The Journal of Neuroscience. 2005; 25: 10717-10728
        • Han J.S.
        • Adwanikar H.
        • Li Z.
        • Ji G.
        • Neugebauer V.
        Facilitation of synaptic transmission and pain responses by CGRP in the amygdala of normal rats.
        Mol Pain. 2010; 6
        • Okutsu Y.
        • Takahashi Y.
        • Nagase M.
        • Shinohara K.
        • Ikeda R.
        • Kato F.
        Potentiation of NMDA receptor-mediated synaptic transmission at the parabrachial-central amygdala synapses by CGRP in mice.
        Mol Pain. 2017; 13: 1-11
      12. Sugimoto M, Takahashi Y, Sugimura YK, Tokunaga R, Yajima M, Kato F (2021): Active role of the central amygdala in widespread mechanical sensitization in rats with facial inflammatory pain. Pain.

        • Xu W.
        • Lundeberg T.
        • Wang Y.T.
        • Li Y.
        • Yu L.C.
        Antinociceptive effect of calcitonin gene-related peptide in the central nucleus of amygdala: Activating opioid receptors through amygdala-periaqueductal gray pathway.
        Neuroscience. 2003; 118: 1015-1022
        • Butler R.K.
        • Ehling S.
        • Barbar M.
        • Thomas J.
        • Hughes M.A.
        • Smith C.E.
        • et al.
        Distinct neuronal populations in the basolateral and central amygdala are activated with acute pain, conditioned fear, and fear-conditioned analgesia.
        Neurosci Lett. 2017; 661: 11-17
        • Ji G.
        • Neugebauer V.
        Differential effects of CRF1 and CRF2 receptor antagonists on pain-related sensitization of neurons in the central nucleus of the amygdala.
        J Neurophysiol. 2007; 97: 3893-3904
      13. Neugebauer V, Mazzitelli M, Cragg B, Ji G, Navratilova E, Porreca F (2020): Amygdala, neuropeptides, and chronic pain-related affective behaviors. Neuropharmacology 108052.

        • Gonçalves L.
        • Dickenson A.H.
        Asymmetric time-dependent activation of right central amygdala neurones in rats with peripheral neuropathy and pregabalin modulation.
        European Journal of Neuroscience. 2012; 36: 3204-3213
        • As-Sanie S.
        • Harris R.E.
        • Napadow V.
        • Kim J.
        • Neshewat G.
        • Kairys A.
        • et al.
        Changes in regional gray matter volume in women with chronic pelvic pain: A voxel-based morphometry study.
        Pain. 2012; 153: 1006-1014
        • Chiang M.C.
        • Nguyen E.K.
        • Canto-Bustos M.
        • Papale A.E.
        • Oswald A.M.M.
        • Ross S.E.
        Divergent Neural Pathways Emanating from the Lateral Parabrachial Nucleus Mediate Distinct Components of the Pain Response.
        Neuron. 2020; 106 (e5): 927-939
        • Han S.
        • Soleiman M.
        • Soden M.
        • Zweifel L.
        • Palmiter R.D.
        Elucidating an Affective Pain Circuit that Creates a Threat Memory.
        Cell. 2015; 162: 363-374
        • Corder G.
        • Ahanonu B.
        • Grewe B.F.
        • Wang D.
        • Schnitzer M.J.
        • Scherrer G.
        An amygdalar neural ensemble that encodes the unpleasantness of pain.
        Science. 2019; 363