Research progress on the mechanisms of pain empathy

Abstract

Recent research has highlighted the indispensability of traditional molecular biology and imaging techniques in pain research. However, the mechanisms underlying pain empathy remain unclear. Consequently, a deeper understanding of these mechanisms would greatly enhance pain management. This article aimed to scrutinize previous research findings on pain empathy, with a particular emphasis on the correlation between empathy for pain and distinct anatomical structures, such as mirror neurons, the anterior cingulate cortex, insular cortex, prefrontal cortex, and amygdala. Additionally, this study explored the involvement of endogenous systems, including oxytocin and the locus coeruleus norepinephrine system, hypothalamic–pituitary–adrenal axis, opioid system, and 5-hydroxylamine signaling. In conclusion, the mechanisms of pain empathy are complex and diverse, and research on pain empathy and target treatment will contribute to pain treatment.

Keywords

empathic response / mirror neurons / neural mechanisms / pain / pain empathy

References

[1] Preston SD, de Waal FBM. Only the PAM explains the personalized nature of empathy. Nat Rev Neurosci. 2017; 18(12): 769.

[2] Ren Q, Lu X, Zhao Q, Zhang H, Hu L. Can self-pain sensitivity quantify empathy for others' pain? Psychophysiology. 2020; 57(10):e13637.

[3] Richardson H, Lisandrelli G, Riobueno-Naylor A, Saxe R. Development of the social brain from age three to twelve years. Nat Commun. 2018; 9(1): 1027.

[4] Church RM. Emotional reactions of rats to the pain of others. J Comp Physiol Psychol. 1959; 52(2): 132-134.

[5] Langford DJ, Crager SE, Shehzad Z, et al. Social modulation of pain as evidence for empathy in mice. Science. 2006; 312(5782): 1967-1970.

[6] Toyoshima M, Okuda E, Hasegawa N, Kaseda K, Yamada K. Socially transferred stress experience modulates social affective behaviors in rats. Neuroscience. 2022; 502: 68-76.

[7] Langford DJ, Bailey AL, Chanda ML, et al. Coding of facial expressions of pain in the laboratory mouse. Nat Methods. 2010; 7(6): 447-449.

[8] Martin LJ, Tuttle AH, Mogil JS. The interaction between pain and social behavior in humans and rodents. Curr Top Behav Neurosci. 2014; 20: 233-250.

[9] Li Z, Lu YF, Li CL, et al. Social interaction with a cagemate in pain facilitates subsequent spinal nociception via activation of the medial prefrontal cortex in rats. Pain. 2014; 155(7): 1253-1261.

[10] Singer T, Seymour B, O'Doherty J, Kaube H, Dolan RJ, Frith CD. Empathy for pain involves the affective but not sensory components of pain. Science. 2004; 303(5661): 1157-1162.

[11] Corradi-Dell'Acqua C, Tusche A, Vuilleumier P, Singer T. Cross-modal representations of first-hand and vicarious pain, disgust and fairness in insular and cingulate cortex. Nat Commun. 2016; 7:10904.

[12] Jauniaux J, Khatibi A, Rainville P, Jackson PL. A meta-analysis of neuroimaging studies on pain empathy: investigating the role of visual information and observers' perspective. Soc Cogn Affect Neurosci. 2019; 14(8): 789-813.

[13] Timmers I, Park AL, Fischer MD, et al. Is empathy for pain unique in its neural correlates? A meta-analysis of neuroimaging studies of empathy. Front Behav Neurosci. 2018; 12:289.

[14] Xiong RC, Fu X, Wu LZ, et al. Brain pathways of pain empathy activated by pained facial expressions: a meta-analysis of fMRI using the activation likelihood estimation method. Neural Regen Res. 2019; 14(1): 172-178.

[15] Chen T, Taniguchi W, Chen QY, et al. Top-down descending facilitation of spinal sensory excitatory transmission from the anterior cingulate cortex. Nat Commun. 2018; 9(1): 1886.

[16] Carrillo M, Han Y, Migliorati F, Liu M, Gazzola V, Keysers C. Emotional mirror neurons in the rat's anterior cingulate cortex. Curr Biol. 2019; 29(8): 1301-1312.e6.

[17] Li L, Zhang LZ, He ZX, et al. Dorsal raphe nucleus to anterior cingulate cortex 5-HTergic neural circuit modulates consolation and sociability. eLife. 2021; 10:e67638.

[18] Smith ML, Asada N, Malenka RC. Anterior cingulate inputs to nucleus accumbens control the social transfer of pain and analgesia. Science. 2021; 371(6525): 153-159.

[19] Gamal-Eltrabily M, Espinosa de los monteros-Zúñiga A, Manzano-García A, Martínez-Lorenzana G, Condés-Lara M, González-Hernández A. The rostral agranular insular cortex, a new site of oxytocin to induce antinociception. J Neurosci. 2020; 40(29): 5669-5680.

[20] Benassi-Cezar G, Carmona IM, Baptista-de-Souza D, Nunes-de-Souza RL, Canto-de-Souza A. Differential modulation of the anterior cingulate and insular cortices on anxiogenic-like responses induced by empathy for pain. Neuropharmacology. 2021; 192:108413.

[21] Mu J, Wang Q, Dun W, et al. The effects of long-term menstrual pain on pain empathy in women with primary dysmenorrhea. Pain. 2021; 162(7): 2051-2059.

[22] Zhang MM, Geng AQ, Chen K, et al. Glutamatergic synapses from the insular cortex to the basolateral amygdala encode observational pain. Neuron. 2022; 110(12): 1993-2008.e6.

[23] Avale ME, Chabout J, Pons S, et al. Prefrontal nicotinic receptors control novel social interaction between mice. FASEB J. 2011; 25(7): 2145-2155.

[24] Ng X, Ng LY, Gabrieli G, Azhari A, Neoh MJY, Esposito G. An fNIRS investigation of masculinity, femininity, and sex on nonparents' empathic response to infant cries. Brain Sci. 2021; 11(5):635.

[25] Bruneau EG, Jacoby N, Saxe R. Empathic control through coordinated interaction of amygdala, theory of mind and extended pain matrix brain regions. Neuroimage. 2015; 114: 105-119.

[26] Rodrigues Tavares LR, Pelarin V, Baptista-de-Souza D, Pereira Ferrari D, Nunes-de-Souza RL, Canto-de-Souza A. 5-HT(3) receptor within the amygdaloid complex modulates pain hypersensitivity induced by empathy model of cohabitation with a partner in chronic pain condition in mice. Soc Neurosci. 2021; 16(5): 534-548.

[27] Rodrigues Tavares LR, Baptista-de-Souza D, Canto-de-Souza L, et al. The reversal of empathy-induced hypernociception in male mice by intra-amygdala administration of midazolam and cannabidiol depends on 5-HT(3) receptors. Cannabis Cannabinoid Res. 2022; 8(2): 335-347.

[28] Travassos C, Sayal A, Direito B, Castelhano J, Castelo-Branco M. Volitional modulation of the left DLPFC neural activity based on a pain empathy Paradigm-A potential novel therapeutic target for pain. Front Neurol. 2020; 11:714.

[29] Xiang Y, Wang Y, Gao S, Zhang X, Cui R. Neural mechanisms with respect to different paradigms and relevant regulatory factors in empathy for pain. Front Neurosci. 2018; 12:507.

[30] Peyron R, Laurent B, García-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin. 2000; 30(5): 263-288.

[31] Lamm C, Decety J, Singer T. Meta-analytic evidence for common and distinct neural networks associated with directly experienced pain and empathy for pain. Neuroimage. 2011; 54(3): 2492-2502.

[32] Valet M, Sprenger T, Boecker H, et al. Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during. Pain. 2004; 109(3): 399-408.

[33] Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron. 2007; 55(3): 377-391.

[34] Stevens RT, London SM, Vania Apkarian A. Spinothalamocortical projections to the secondary somatosensory cortex (SII) in squirrel monkey. Brain Res. 1993; 631(2): 241-246.

[35] Guo X, Zheng L, Zhang W, et al. Empathic neural responses to others' pain depend on monetary reward. Soc Cogn Affect Neurosci. 2012; 7(5): 535-541.

[36] Xu X, Zuo X, Wang X, Han S. Do you feel my pain? Racial group membership modulates empathic neural responses. J Neurosci. 2009; 29(26): 8525-8529.

[37] Cheng Y, Yang CY, Lin CP, Lee PL, Decety J. The perception of pain in others suppresses somatosensory oscillations: a magnetoencephalography study. Neuroimage. 2008; 40(4): 1833-1840.

[38] Rizzolatti G, Luppino G. The cortical motor system. Neuron. 2001; 31(6): 889-901.

[39] Betti V, Zappasodi F, Rossini PM, Aglioti SM, Tecchio F. Synchronous with your feelings: sensorimotor γ band and empathy for pain. J Neurosci. 2009; 29(40): 12384-12392.

[40] Vecchio A, De Pascalis V. ERP indicators of situational empathy pain. Behav Brain Res. 2023; 439:114224.

[41] Decety J, Yang CY, Cheng Y. Physicians down-regulate their pain empathy response: an event-related brain potential study. Neuroimage. 2010; 50(4): 1676-1682.

[42] Cheng Y, Hung AY, Decety J. Dissociation between affective sharing and emotion understanding in juvenile psychopaths. Dev Psychopathol. 2012; 24(2): 623-636.

[43] Bonini L, Rotunno C, Arcuri E, Gallese V. Mirror neurons 30 years later: implications and applications. Trends Cogn Sci. 2022; 26(9): 767-781.

[44] di Pellegrino G, Fadiga L, Fogassi L, Gallese V, Rizzolatti G. Understanding motor events: a neurophysiological study. Exp Brain Res. 1992; 91(1): 176-180.

[45] Pineda JA. Sensorimotor cortex as a critical component of an ‘extended’ mirror neuron system: does it solve the development, correspondence, and control problems in mirroring. Behav Brain Funct. 2008; 4:47.

[46] Plata-Bello J, Privato N, Modroño C, Pérez-Martín Y, Borges Á, González-Mora JL. Empathy modulates the activity of the sensorimotor mirror neuron system during pain observation. Behav Sci. 2023; 13(11):947.

[47] Bekkali S, Youssef GJ, Donaldson PH, Albein-Urios N, Hyde C, Enticott PG. Is the putative mirror neuron system associated with empathy? A systematic review and meta-analysis. Neuropsychol Rev. 2021; 31(1): 14-57.

[48] Wu WY, Cheng Y, Liang KC, Lee RX, Yen CT. Affective mirror and anti-mirror neurons relate to prosocial help in rats. iScience. 2023; 26(1):105865.

[49] Zaniboni CR, Pelarin V, Baptista-de-Souza D, Canto-de-Souza A. Empathy for pain: insula inactivation and systemic treatment with midazolam reverses the hyperalgesia induced by cohabitation with a pair in chronic pain condition. Front Behav Neurosci. 2018; 12:278.

[50] Penagos-Corzo JC, Cosio van-Hasselt M, Escobar D, Vázquez-Roque RA, Flores G. Mirror neurons and empathy-related regions in psychopathy: systematic review, meta-analysis, and a working model. Soc Neurosci. 2022; 17(5): 462-479.

[51] Rizzolatti G, Craighero L. The mirror-neuron system. Annu Rev Neurosci. 2004; 27: 169-192.

[52] Muthukumaraswamy SD, Johnson BW, McNair NA. Mu rhythm modulation during observation of an object-directed grasp. Cogn Brain Res. 2004; 19(2): 195-201.

[53] Oberman LM, Hubbard EM, McCleery JP, Altschuler EL, Ramachandran VS, Pineda JA. EEG evidence for mirror neuron dysfunction in autism spectrum disorders. Cogn Brain Res. 2005; 24(2): 190-198.

[54] Pascual-Leone A. Transcranial magnetic stimulation: studying the brain-behaviour relationship by induction of ‘virtual lesions’. Philos Trans R Soc London [Biol]. 1999; 354(1387): 1229-1238.

[55] Fuelscher I, Caeyenberghs K, Enticott PG, et al. Does fMRI repetition suppression reveal mirror neuron activity in the human brain? Insights from univariate and multivariate analysis. Eur J Neurosci. 2019; 50(5): 2877-2892.

[56] Carrillo M, Han Y, Migliorati F, Liu M, Gazzola V, Keysers C. Emotional mirror neurons in the rat's anterior cingulate cortex. Curr Biol. 2019; 29(12):2104.

[57] Friesner ID, Martinez E, Zhou H, et al. Ketamine normalizes high-gamma power in the anterior cingulate cortex in a rat chronic pain model. Mol Brain. 2020; 13(1): 129.

[58] Sakaguchi T, Iwasaki S, Okada M, Okamoto K, Ikegaya Y. Ethanol facilitates socially evoked memory recall in mice by recruiting pain-sensitive anterior cingulate cortical neurons. Nat Commun. 2018; 9(1): 3526.

[59] Xiao X, Zhang YQ. A new perspective on the anterior cingulate cortex and affective pain. Neurosci Biobehav Rev. 2018; 90: 200-211.

[60] Choi S, Kim K, Kwon M, Bai SJ, Cha M, Lee BH. Modulation of neuropathic pain by glial regulation in the insular cortex of rats. Front Mol Neurosci. 2022; 15:815945.

[61] Hsieh JC, Belfrage M, Stone-Elander S, Hansson P, Ingvar M. Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain. 1995; 63(2): 225-236.

[62] Lu C, Yang T, Zhao H, et al. Insular cortex is critical for the perception, modulation, and chronification of pain. Neurosci Bull. 2016; 32(2): 191-201.

[63] Matsumoto M, Yoshida M, Jayathilake BW, et al. Indispensable role of the oxytocin receptor for allogrooming toward socially distressed cage mates in female mice. J Neuroendocrinol. 2021; 33(6):e12980.

[64] Geng KW, He T, Wang RR, et al. Ethanol increases mechanical pain sensitivity in rats via activation of GABAA receptors in medial prefrontal cortex. Neurosci Bull. 2016; 32(5): 433-444.

[65] Domínguez-Arriola ME, Olalde-Mathieu VE, Garza-Villarreal EA, Barrios FA. The dorsolateral prefrontal cortex presents structural variations associated with empathy and emotion regulation in psychotherapists. Brain Topogr. 2022; 35(5-6): 613-626.

[66] Laneri D, Krach S, Paulus FM, et al. Mindfulness meditation regulates anterior insula activity during empathy for social pain. Hum Brain Mapp. 2017; 38(8): 4034-4046.

[67] Yuan B, Tolomeo S, Yang C, Wang Y, Yu R. tDCS effect on prosocial behavior: a meta-analytic review. Soc Cogn Affect Neurosci. 2022; 17(1): 26-42.

[68] Wang J, Wang Y, Hu Z, Li X. Transcranial direct current stimulation of the dorsolateral prefrontal cortex increased pain empathy. Neuroscience. 2014; 281: 202-207.

[69] Sato M, Nakai N, Fujima S, Choe KY, Takumi T. Social circuits and their dysfunction in autism spectrum disorder. Mol Psychiatry. 2023; 28(8): 3194-3206.

[70] Ong WY, Stohler CS, Herr DR. Role of the prefrontal cortex in pain processing. Mol Neurobiol. 2019; 56(2): 1137-1166.

[71] Kandis S, Ates M, Kizildag S, et al. Acetaminophen (paracetamol) affects empathy-like behavior in rats: dose-response relationship. Pharmacol Biochem Behav. 2018; 175: 146-151.

[72] Sheng F, Liu Y, Zhou B, Zhou W, Han S. Oxytocin modulates the racial bias in neural responses to others' suffering. Biol Psychol. 2013; 92(2): 380-386.

[73] Han S. Neurocognitive basis of racial ingroup bias in empathy. Trends Cogn Sci. 2018; 22(5): 400-421.

[74] Filippa M, Monaci MG, Spagnuolo C, Serravalle P, Daniele R, Grandjean D. Maternal speech decreases pain scores and increases oxytocin levels in preterm infants during painful procedures. Sci Rep. 2021; 11(1):17301.

[75] George JM. Immunoreactive vasopressin and oxytocin: concentration in individual human hypothalamic nuclei. Science. 1978; 200(4339): 342-343.

[76] Takahashi J, Yamada D, Nagano W, Sano Y, Furuichi T, Saitoh A. Oxytocinergic projection from the hypothalamus to supramammillary nucleus drives recognition memory in mice. PLoS ONE. 2023; 18(11):e0294113.

[77] Menon R, Grund T, Zoicas I, et al. Oxytocin signaling in the lateral septum prevents social fear during lactation. Curr Biol. 2018; 28(7): 1066-1078.e6.

[78] Laviola G, Busdraghi LM, Meschino N, Petrella C, Fiore M. Aberrant early in life stimulation of the stress-response system affects emotional contagion and oxytocin regulation in adult male mice. Int J Mol Sci. 2021; 22(9):5039.

[79] Montag C, Schöner J, Speck LG, et al. Peripheral oxytocin is inversely correlated with cognitive, but not emotional empathy in schizophrenia. PLoS ONE. 2020; 15(4):e0231257.

[80] Lin C, Zhuo S, Zheng Q, Li X, Peng W. The relationship between oxytocin and empathy for others' pain: testing the mediating effect of first-hand pain sensitivity. Physiol Behav. 2023; 269:114266.

[81] Mayer AV, Wermter AK, Stroth S, et al. Randomized clinical trial shows no substantial modulation of empathy-related neural activation by intranasal oxytocin in autism. Sci Rep. 2021; 11(1):15056.

[82] Luo S, Zhang T, Li W, Yu M, Hein G, Han S. Interactions between oxytocin receptor gene and intergroup relationship on empathic neural responses to others' pain. Soc Cogn Affect Neurosci. 2019; 14(5): 505-517.

[83] Llorca-Torralba M, Camarena-Delgado C, Suárez-Pereira I, et al. Pain and depression comorbidity causes asymmetric plasticity in the locus coeruleus neurons. Brain. 2022; 145(1): 154-167.

[84] Suto T, Eisenach JC, Hayashida K. Peripheral nerve injury and gabapentin, but not their combination, impair attentional behavior via direct effects on noradrenergic signaling in the brain. Pain. 2014; 155(10): 1935-1942.

[85] Breton-Provencher V, Drummond GT, Sur M. Locus coeruleus norepinephrine in learned behavior: anatomical modularity and spatiotemporal integration in targets. Front Neural Circuits. 2021; 15:638007.

[86] Yu Y, Li CL, Du R, Chen J. Rat model of empathy for pain. Bio Protoc. 2019; 9(12):e3266.

[87] Lu YF, Zhang J, Wang XQ, et al. Noradrenergic innervations of the medial prefrontal cortex mediate empathy for pain in rats via the α1 and β receptors. Behav Brain Res. 2022; 426:113828.

[88] Heckenberg RA, Hale MW, Kent S, Wright BJ. Empathy and job resources buffer the effect of higher job demands on increased salivary alpha amylase awakening responses in direct-care workers. Behav Brain Res. 2020; 394:112826.

[89] Karakilic A, Kizildag S, Kandis S, et al. The effects of acute foot shock stress on empathy levels in rats. Behav Brain Res. 2018; 349: 31-36.

[90] Daviu N, Bruchas MR, Moghaddam B, Sandi C, Beyeler A. Neurobiological links between stress and anxiety. Neurobiol Stress. 2019; 11:100191.

[91] Zoratto F, Sbriccoli M, Martinelli A, Glennon JC, Macrì S, Laviola G. Intranasal oxytocin administration promotes emotional contagion and reduces aggression in a mouse model of callousness. Neuropharmacology. 2018; 143: 250-267.

[92] Karjalainen T, Karlsson HK, Lahnakoski JM, et al. Dissociable roles of cerebral μ-Opioid and type 2 dopamine receptors in vicarious pain: a combined PET–fMRI study. Cereb Cortex. 2017; 27(8): 4257-4266.

[93] Nazeri M, Chamani G, Abareghi F, et al. Sensory and affective dimensions of pain and anxiety like behaviors are altered in an animal model of pain empathy. Iran J Psychiatry. 2019; 14(3): 221-226.

[94] Peciña M, Karp JF, Mathew S, Todtenkopf MS, Ehrich EW, Zubieta JK. Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches. Mol Psychiatry. 2019; 24(4): 576-587.

[95] Rütgen M, Wirth EM, Riečanský I, et al. Beyond sharing unpleasant affect-evidence for pain-specific opioidergic modulation of empathy for pain. Cereb Cortex. 2021; 31(6): 2773-2786.

[96] Kroll SL, Thayer JF, Williams DP, et al. Chronic non-medical prescription opioid use and empathy for pain: does pain make the difference? Psychophysiology. 2021; 58(4):e13776.

[97] Zhao Y, Rütgen M, Zhang L, Lamm C. Pharmacological fMRI provides evidence for opioidergic modulation of discrimination of facial pain expressions. Psychophysiology. 2021; 58(2):e13717.

[98] Mousavi A, Askari N, Vaez-Mahdavi MR. Augmentation of morphine-conditioned place preference by food restriction is associated with alterations in the oxytocin/oxytocin receptor in rat models. Am J Drug Alcohol Abuse. 2020; 46(3): 304-315.

[99] Costa-Pereira JT, Serrão P, Martins I, Tavares I. Serotoninergic pain modulation from the rostral ventromedial medulla (RVM) in chemotherapy-induced neuropathy: the role of spinal 5-HT3 receptors. Eur J Neurosci. 2020; 51(8): 1756-1769.

[100] Hoyer D. Targeting the 5-HT system: potential side effects. Neuropharmacology. 2020; 179:108233.

[101] Ji G, Neugebauer V. Contribution of corticotropin-releasing factor receptor 1 (CRF1) to serotonin receptor 5-HT2CR function in amygdala neurons in a neuropathic pain model. Int J Mol Sci. 2019; 20(18):4380.

[102] Zhao R, Ji Y, Li J, et al. Pain empathy and its association with the clinical pain in knee osteoarthritis patients. J Pain Res. 2022; 15: 4017-4027.

[103] Fallon N, Li X, Chiu Y, Nurmikko T, Stancak A. Altered cortical processing of observed pain in patients with fibromyalgia syndrome. J Pain. 2015; 16(8): 717-726.

[104] Jelsone-Swain L, McCommon SA, Turk B, Roach A. Acetaminophen changes Mu rhythm power related to pain empathy. Neuropsychologia. 2023; 184:108544.

[105] Gong P, Liu J, Li S, Zhou X. Dopamine beta-hydroxylase gene modulates individuals' empathic ability. Soc Cogn Affect Neurosci. 2014; 9(9): 1341-1345.

[106] Lü YF, Yang Y, Li CL, Wang Y, Li Z, Chen J. The locus coeruleus-norepinephrine system mediates empathy for pain through selective up-regulation of P2X3 receptor in dorsal root ganglia in rats. Front Neural Circuits. 2017; 11:66.

RIGHTS & PERMISSIONS

2024 The Author(s). Ibrain published by Affiliated Hospital of Zunyi Medical University and Wiley-VCH GmbH.