The sensory, associative and limbic neocortical structures play a critical role in shaping incoming noxious inputs to generate variable pain perceptions. Technological advances in tracing circuitry and interrogation of pathways and complex behaviours are now yielding critical knowledge of neocortical circuits, cellular contributions and causal relationships between pain perception and its abnormalities in chronic pain. Emerging insights into neocortical pain processing suggest the existence of neocortical causality and specificity for pain at the level of subdomains, circuits and cellular entities and the activity patterns they encode. These mechanisms provide opportunities for therapeutic intervention for improved pain management.
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Baliki, M. N. & Apkarian, A. V. Nociception, pain, negative moods, and behavior selection. Neuron 87, 474–491 (2015).
Wager, T. D. et al. An fMRI-based neurologic signature of physical pain. N. Engl. J. Med. 368, 1388–1397 (2013).
Bushnell, M. C., Ceko, M. & Low, L. A. Cognitive and emotional control of pain and its disruption in chronic pain. Nat. Rev. Neurosci. 14, 502–511 (2013).
Kuner, R. & Flor, H. Structural plasticity and reorganisation in chronic pain. Nat. Rev. Neurosci. 18, 20–30 (2016).
Kuner, R. & Kuner, T. Cellular circuits in the brain and their modulation in acute and chronic pain. Physiol. Rev. 101, 213–258 (2020).
Braz, J., Solorzano, C., Wang, X. & Basbaum, A. I. Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. Neuron 82, 522–536 (2014).
Peirs, C. & Seal, R. P. Neural circuits for pain: recent advances and current views. Science 354, 578–584 (2016).
Finnerup, N. B., Kuner, R. & Jensen, T. S. Neuropathic pain: from mechanisms to treatment. Physiol. Rev. 101, 259–301 (2020).
Seminowicz, D. A. & Moayedi, M. The dorsolateral prefrontal cortex in acute and chronic pain. J. Pain 18, 1027–1035 (2017).
Woo, C. W. et al. Quantifying cerebral contributions to pain beyond nociception. Nat. Commun. 8, 14211 (2017). In this study, functional imaging, multivariate pattern analysis and machine learning approaches are used to identify the nature of cerebral regions that are activated in a stimulus intensity-independent manner to predict pain beyond nociceptive input and help explain how psychological manipulations and expectation modulate pain.
Da Silva, J. T. & Seminowicz, D. A. Neuroimaging of pain in animal models: a review of recent literature. Pain. Rep. 4, e732 (2019).
Carlen, M. What constitutes the prefrontal cortex? Science 358, 478–482 (2017).
Laubach, M., Amarante, L. M., Swanson, K. & White, S. R. What, if anything, is rodent prefrontal cortex? eNeuro 5, ENEURO.0315-18.2018 (2018).
Shiers, S. & Price, T. J. Molecular, circuit, and anatomical changes in the prefrontal cortex in chronic pain. Pain 161, 1726–1729 (2020).
Apkarian, A. V., Baliki, M. N. & Farmer, M. A. Predicting transition to chronic pain. Curr. Opin. Neurol. 26, 360–367 (2013).
Schulz, E. et al. Prefrontal gamma oscillations encode tonic pain in humans. Cereb. Cortex 25, 4407–4414 (2015).
Ploner, M., Sorg, C. & Gross, J. Brain rhythms of pain. Trends Cogn. Sci. 21, 100–110 (2017).
Kim, J. A. & Davis, K. D. Neural oscillations: understanding a neural code of pain. Neuroscientist https://doi.org/10.1177/1073858420958629 (2020).
Baliki, M. N. et al. Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J. Neurosci. 26, 12165–12173 (2006).
Hashmi, J. A. et al. Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits. Brain 136, 2751–2768 (2013).
May, E. S. et al. Prefrontal gamma oscillations reflect ongoing pain intensity in chronic back pain patients. Hum. Brain Mapp. 40, 293–305 (2019).
Ta Dinh, S. et al. Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography. Pain 160, 2751–2765 (2019).
Dale, J. et al. Scaling up cortical control inhibits pain. Cell Rep. 23, 1301–1313 (2018).
Thompson, J. M. & Neugebauer, V. Cortico-limbic pain mechanisms. Neurosci. Lett. 702, 15–23 (2019).
Wang, G. Q. et al. Deactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety. Nat. Commun. 6, 7660 (2015).
Jiang, Z. C. et al. Inactivation of the prelimbic rather than infralimbic cortex impairs acquisition and expression of formalin-induced conditioned place avoidance. Neurosci. Lett. 569, 89–93 (2014).
Cheriyan, J. & Sheets, P. L. Altered excitability and local connectivity of mPFC-PAG neurons in a mouse model of neuropathic pain. J. Neurosci. 38, 4829–4839 (2018).
Fan, X. C. et al. Hypersensitivity of prelimbic cortex neurons contributes to aggravated nociceptive responses in rats with experience of chronic inflammatory pain. Front. Mol. Neurosci. 11, 85 (2018).
Tan, L. L. et al. A pathway from midcingulate cortex to posterior insula gates nociceptive hypersensitivity. Nat. Neurosci. 20, 1591–1601 (2017). In this study, the authors reveal the importance of an excitatory pathway from the MCC to the PI and subsequently the raphe nucleus, which recruits descending serotonergic facilitatory projections to the spinal cord to influence peripheral nociceptive responses.
Mitric, M. et al. Layer- and subregion-specific electrophysiological and morphological changes of the medial prefrontal cortex in a mouse model of neuropathic pain. Sci. Rep. 9, 9479 (2019).
Zhang, Z. et al. Role of prelimbic GABAergic circuits in sensory and emotional aspects of neuropathic pain. Cell Rep. 12, 752–759 (2015).
Kelly, C. J., Huang, M., Meltzer, H. & Martina, M. Reduced glutamatergic currents and dendritic branching of layer 5 pyramidal cells contribute to medial prefrontal cortex deactivation in a rat model of neuropathic pain. Front. Cell Neurosci. 10, 133 (2016).
Huang, J. et al. A neuronal circuit for activating descending modulation of neuropathic pain. Nat. Neurosci. 22, 1659–1668 (2019). This study reports that the synaptic input from the BLA on to GABAergic interneurons in the PL cortex is enhanced upon nerve injury via reduced endocannabinoid signalling. This results in enhanced feedforward inhibition of prefrontal neurons that project to the ventrolateral PAG and thereby alters descending noradrenergic and serotonergic pathways.
Jones, A. F. & Sheets, P. L. Sex-specific disruption of distinct mPFC inhibitory neurons in spared-nerve injury model of neuropathic pain. Cell Rep. 31, 107729 (2020). This study is the first to demonstrate that chronic neuropathic pain is modulated in a sex-specific manner involving alterations of distinct subclasses of GABAergic neurons that differ between the male mouse PL cortex and the female mouse PL cortex.
Huang, S., Borgland, S. L. & Zamponi, G. W. Dopaminergic modulation of pain signals in the medial prefrontal cortex: challenges and perspectives. Neurosci. Lett. 702, 71–76 (2019).
Naser, P. V. & Kuner, R. Molecular, cellular and circuit basis of cholinergic modulation of pain. Neuroscience 387, 135–148 (2018).
Metz, A. E., Yau, H. J., Centeno, M. V., Apkarian, A. V. & Martina, M. Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain. Proc. Natl Acad. Sci. USA 106, 2423–2428 (2009).
Cordeiro Matos, S., Zamfir, M., Longo, G., Ribeiro-da-Silva, A. & Seguela, P. Noradrenergic fiber sprouting and altered transduction in neuropathic prefrontal cortex. Brain Struct. Funct. 223, 1149–1164 (2018).
Cordeiro Matos, S., Zhang, Z. & Seguela, P. Peripheral neuropathy induces HCN channel dysfunction in pyramidal neurons of the medial prefrontal cortex. J. Neurosci. 35, 13244–13256 (2015). This study reports that nerve injury leads to a dysfunction of HCN channels in the dendrites of layer 2/3 pyramidal neurons in the mPFC, resulting in enhanced excitability and neuronal firing. An altered cAMP–PKA axis was suggested to underlie alterations to HCN channel function.
Shiers, S. et al. Neuropathic pain creates an enduring prefrontal cortex dysfunction corrected by the type II diabetic drug metformin but not by gabapentin. J. Neurosci. 38, 7337–7350 (2018).
Baliki, M. N. et al. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat. Neurosci. 15, 1117–1119 (2012).
Lee, M. et al. Activation of corticostriatal circuitry relieves chronic neuropathic pain. J. Neurosci. 35, 5247–5259 (2015).
Martinez, E. et al. Corticostriatal regulation of acute pain. Front. Cell Neurosci. 11, 146 (2017).
Zhou, H. et al. Inhibition of the prefrontal projection to the nucleus accumbens enhances pain sensitivity and affect. Front. Cell Neurosci. 12, 240 (2018).
Coulombe, M. A., Erpelding, N., Kucyi, A. & Davis, K. D. Intrinsic functional connectivity of periaqueductal gray subregions in humans. Hum. Brain Mapp. 37, 1514–1530 (2016).
Ferreira, A. N., Yousuf, H., Dalton, S. & Sheets, P. L. Highly differentiated cellular and circuit properties of infralimbic pyramidal neurons projecting to the periaqueductal gray and amygdala. Front. Cell Neurosci. 9, 161 (2015).
Yin, J. B. et al. dmPFC-vlPAG projection neurons contribute to pain threshold maintenance and antianxiety behaviors. J. Clin. Invest. 130, 6555–6570 (2020). This study further highlights the importance of prefrontal cortical influences on descending pain modulatory systems in pain and their dysregulation in neuropathic pain, reporting an excitatory pathway from the dorsomedial PFC to the ventrolateral PAG, which, upon activation, reduces nociception as well as anxiety-related behaviours in neuropathic mice.
Vachon-Presseau, E. et al. Corticolimbic anatomical characteristics predetermine risk for chronic pain. Brain 139, 1958–1970 (2016).
Kiritoshi, T. & Neugebauer, V. Pathway-specific alterations of cortico-amygdala transmission in an arthritis pain model. ACS Chem. Neurosci. 9, 2252–2261 (2018).
Vogt, B. A. Submodalities of emotion in the context of cingulate subregions. Cortex 59, 197–202 (2014).
Vogt, B. A. Cingulate Neurobiology and Disease (Oxford Univ. Press, 2009).
Blom, S. M., Pfister, J. P., Santello, M., Senn, W. & Nevian, T. Nerve injury-induced neuropathic pain causes disinhibition of the anterior cingulate cortex. J. Neurosci. 34, 5754–5764 (2014).
Johansen, J. P. & Fields, H. L. Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal. Nat. Neurosci. 7, 398–403 (2004).
Fuchs, P. N., Peng, Y. B., Boyette-Davis, J. A. & Uhelski, M. L. The anterior cingulate cortex and pain processing. Front. Integr. Neurosci. 8, 35 (2014).
Bliss, T. V., Collingridge, G. L., Kaang, B. K. & Zhuo, M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat. Rev. Neurosci. 17, 485–496 (2016).
Kragel, P. A. et al. Generalizable representations of pain, cognitive control, and negative emotion in medial frontal cortex. Nat. Neurosci. 21, 283–289 (2018). This study uses functional imaging and multivariate pattern analysis to determine that pain representations were localized to the anterior MCC, negative emotion representations were more common in the ventromedial PFC and cognitive control representations were localized to parts of the dorsal MCC, thus suggesting domain-specific representations for pain, negative emotion and cognitive control in the mPFC.
Shackman, A. J. et al. The integration of negative affect, pain and cognitive control in the cingulate cortex. Nat. Rev. Neurosci. 12, 154–167 (2011).
Strauss, I. et al. Double anterior stereotactic cingulotomy for intractable oncological pain. Stereotact. Funct. Neurosurg. 95, 400–408 (2017).
Fitzgerald, J. M. et al. DACC resting state functional connectivity as a predictor of pain symptoms following motor vehicle crash: a preliminary investigation. J. Pain 22, 171–179 (2020).
Edes, A. E. et al. Increased activation of the pregenual anterior cingulate cortex to citalopram challenge in migraine: an fMRI study. BMC Neurol. 19, 237 (2019).
Icenhour, A. et al. Brain functional connectivity is associated with visceral sensitivity in women with irritable bowel syndrome. Neuroimage Clin. 15, 449–457 (2017).
Wang, G., Erpelding, N. & Davis, K. D. Sex differences in connectivity of the subgenual anterior cingulate cortex. Pain 155, 755–763 (2014).
Osborne, N. R. et al. Abnormal subgenual anterior cingulate circuitry is unique to women but not men with chronic pain. Pain 162, 97–108 (2021).
Zhuo, M. Long-term potentiation in the anterior cingulate cortex and chronic pain. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369, 20130146 (2014).
Koga, K. et al. In vivo whole-cell patch-clamp recording of sensory synaptic responses of cingulate pyramidal neurons to noxious mechanical stimuli in adult mice. Mol. Pain 6, 62 (2010).
Meda, K. S. et al. Microcircuit mechanisms through which mediodorsal thalamic input to anterior cingulate cortex exacerbates pain-related aversion. Neuron 102, 944–959.e3 (2019).
Ning, L., Ma, L. Q., Wang, Z. R. & Wang, Y. W. Chronic constriction injury induced long-term changes in spontaneous membrane-potential oscillations in anterior cingulate cortical neurons in vivo. Pain Physician 16, E577–E589 (2013).
Li, X. H., Chen, Q. Y. & Zhuo, M. Neuronal adenylyl cyclase targeting central plasticity for the treatment of chronic pain. Neurotherapeutics 17, 861–873 (2020).
Santello, M. & Nevian, T. Dysfunction of cortical dendritic integration in neuropathic pain reversed by serotoninergic neuromodulation. Neuron 86, 233–246 (2015). This study uses elegant electrophysiological techniques to demonstrate that HCN channel dysfunction in cortical output neurons in layer 5 of the PFC in neuropathic pain can be reversed by serotonergic modulation.
Kang, S. J. et al. Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC. Mol. Brain 8, 81 (2015).
Barthas, F. et al. The anterior cingulate cortex is a critical hub for pain-induced depression. Biol. Psychiatry 77, 236–245 (2015).
Sellmeijer, J. et al. Hyperactivity of anterior cingulate cortex areas 24a/24b drives chronic pain-induced anxiodepressive-like consequences. J. Neurosci. 38, 3102–3115 (2018).
Zhou, H. et al. Ketamine reduces aversion in rodent pain models by suppressing hyperactivity of the anterior cingulate cortex. Nat. Commun. 9, 3751 (2018).
Yao, P. W. et al. Upregulation of tumor necrosis factor-alpha in the anterior cingulate cortex contributes to neuropathic pain and pain-associated aversion. Neurobiol. Dis. 130, 104456 (2019).
Zhang, Q. et al. Chronic pain induces generalized enhancement of aversion. eLife 6, e25302 (2017).
Gao, S. H. et al. The projections from the anterior cingulate cortex to the nucleus accumbens and ventral tegmental area contribute to neuropathic pain-evoked aversion in rats. Neurobiol. Dis. 140, 104862 (2020).
Chen, T. et al. Top-down descending facilitation of spinal sensory excitatory transmission from the anterior cingulate cortex. Nat. Commun. 9, 1886 (2018).
Vogt, B. A. Pain and emotion interactions in subregions of the cingulate gyrus. Nat. Rev. Neurosci. 6, 533–544 (2005). This review provides an excellent overview of the importance of cingulate organization and the implications of specific cingulate subregions in the processing of emotion and nociceptive information.
Almarzouki, A. F., Brown, C. A., Brown, R. J., Leung, M. H. K. & Jones, A. K. P. Negative expectations interfere with the analgesic effect of safety cues on pain perception by priming the cortical representation of pain in the midcingulate cortex. PLoS ONE 12, e0180006 (2017).
Fillinger, C., Yalcin, I., Barrot, M. & Veinante, P. Afferents to anterior cingulate areas 24a and 24b and midcingulate areas 24a’ and 24b’ in the mouse. Brain Struct. Funct. 222, 1509–1532 (2017).
Hu, T. T. et al. Activation of the intrinsic pain inhibitory circuit from the midcingulate Cg2 to zona incerta alleviates neuropathic pain. J. Neurosci. 39, 9130–9144 (2019).
Kim, J. et al. Somatotopically specific primary somatosensory connectivity to salience and default mode networks encodes clinical pain. Pain 160, 1594–1605 (2019).
Tan, L. L. et al. Gamma oscillations in somatosensory cortex recruit prefrontal and descending serotonergic pathways in aversion and nociception. Nat. Commun. 10, 983 (2019).
Yang, P. F., Wu, R., Wu, T. L., Shi, Z. & Chen, L. M. Discrete modules and mesoscale functional circuits for thermal nociception within primate S1 cortex. J. Neurosci. 38, 1774–1787 (2018).
Zhang, Z. G., Hu, L., Hung, Y. S., Mouraux, A. & Iannetti, G. D. Gamma-band oscillations in the primary somatosensory cortex—a direct and obligatory correlate of subjective pain intensity. J. Neurosci. 32, 7429–7438 (2012).
Heid, C. et al. Early gamma-oscillations as correlate of localized nociceptive processing in primary sensorimotor cortex. J. Neurophysiol. 123, 1711–1726 (2020).
Gross, J., Schnitzler, A., Timmermann, L. & Ploner, M. Gamma oscillations in human primary somatosensory cortex reflect pain perception. PLoS Biol. 5, e133 (2007).
Misra, G., Ofori, E., Chung, J. W. & Coombes, S. A. Pain-related suppression of beta oscillations facilitates voluntary movement. Cereb. Cortex 27, 2592–2606 (2017).
Ploner, M., Gross, J., Timmermann, L., Pollok, B. & Schnitzler, A. Pain suppresses spontaneous brain rhythms. Cereb. Cortex 16, 537–540 (2006).
Hu, L. & Iannetti, G. D. Neural indicators of perceptual variability of pain across species. Proc. Natl Acad. Sci. USA 116, 1782–1791 (2019).
Yue, L. P., Iannetti, G. D. & Hu, L. The neural origin of nociceptive-induced gamma band oscillations. J. Neurosci. 40, 2478–3490 (2020).
Wang, J., Wang, J., Xing, G. G., Li, X. & Wan, Y. Enhanced gamma oscillatory activity in rats with chronic inflammatory pain. Front. Neurosci. 10, 489 (2016).
Uhelski, M. L., Davis, M. A. & Fuchs, P. N. Pain affect in the absence of pain sensation: evidence of asomaesthesia after somatosensory cortex lesions in the rat. Pain 153, 885–892 (2012).
Eto, K. et al. Inter-regional contribution of enhanced activity of the primary somatosensory cortex to the anterior cingulate cortex accelerates chronic pain behavior. J. Neurosci. 31, 7631–7636 (2011).
Cichon, J., Blanck, T. J. J., Gan, W. B. & Yang, G. Activation of cortical somatostatin interneurons prevents the development of neuropathic pain. Nat. Neurosci. 20, 1122–1132 (2017).
Andoh, J. et al. Neural correlates of evoked phantom limb sensations. Biol. Psychol. 126, 89–97 (2017).
Jin, Y. et al. A somatosensory cortex input to the caudal dorsolateral striatum controls comorbid anxiety in persistent pain. Pain 161, 416–428 (2020).
Singh, A. et al. Mapping cortical integration of sensory and affective pain pathways. Curr. Biol. 30, 1703–1715.e5 (2020).
Liu, Y. et al. Touch and tactile neuropathic pain sensitivity are set by corticospinal projections. Nature 561, 547–550 (2018).
Abraira, V. E. et al. The cellular and synaptic architecture of the mechanosensory dorsal horn. Cell 168, 295–310.e19 (2017).
Mazzola, L., Isnard, J. & Mauguière, F. Somatosensory and pain responses to stimulation of the second somatosensory area (SII) in humans. A comparison with SI and insular responses. Cereb. Cortex 16, 960–968 (2006).
Liang, M., Mouraux, A. & Iannetti, G. D. Parallel processing of nociceptive and non-nociceptive somatosensory information in the human primary and secondary somatosensory cortices: evidence from dynamic causal modeling of functional magnetic resonance imaging data. J. Neurosci. 31, 8976–8985 (2011).
Garcia-Larrea, L. & Peyron, R. Pain matrices and neuropathic pain matrices: a review. Pain 154, S29–S43 (2013).
Inami, C. et al. Visualization of brain activity in a neuropathic pain model using quantitative activity-dependent manganese magnetic resonance imaging. Front. Neural Circuits 13, 74 (2019).
Zhu, X. et al. A central amygdala input to the parafascicular nucleus controls comorbid pain in depression. Cell Rep. 29, 3847–3858.e5 (2019).
Gogolla, N. The insular cortex. Curr. Biol. 27, R580–R586 (2017).
Garcia-Larrea, L. The posterior insular-opercular region and the search of a primary cortex for pain. Neurophysiol. Clin. 42, 299–313 (2012).
Gehrlach, D. A. et al. Aversive state processing in the posterior insular cortex. Nat. Neurosci. 22, 1424–1437 (2019). In this study, the authors provide comprehensive data to reveal the importance of the PI and its associated circuitries in the detection of aversive internal states and triggering of behavioural adaptations critical for survival in mice.
Mazzola, L., Mauguiere, F. & Isnard, J. Functional mapping of the human insula: data from electrical stimulations. Rev. Neurol. 175, 150–156 (2019).
Liberati, G. et al. Tonic thermonociceptive stimulation selectively modulates ongoing neural oscillations in the human posterior insula: evidence from intracerebral EEG. Neuroimage 188, 70–83 (2019).
Liberati, G. et al. Gamma-band oscillations preferential for nociception can be recorded in the human insula. Cereb. Cortex 28, 3650–3664 (2018).
Frot, M., Faillenot, I. & Mauguiere, F. Processing of nociceptive input from posterior to anterior insula in humans. Hum. Brain Mapp. 35, 5486–5499 (2014).
Bastuji, H., Frot, M., Perchet, C., Hagiwara, K. & Garcia-Larrea, L. Convergence of sensory and limbic noxious input into the anterior insula and the emergence of pain from nociception. Sci. Rep. 8, 13360 (2018).
Li, X. et al. The reorganization of insular subregions in individuals with below-level neuropathic pain following incomplete spinal cord injury. Neural Plast. 2020, 2796571 (2020).
Zhuo, M. Cortical LTP: a synaptic model for chronic pain. Adv. Exp. Med. Biol. 1099, 147–155 (2018).
Miao, H. H., Li, X. H., Chen, Q. Y. & Zhuo, M. Calcium-stimulated adenylyl cyclase subtype 1 is required for presynaptic long-term potentiation in the insular cortex of adult mice. Mol. Pain 15, 1744806919842961 (2019).
Corder, G. et al. An amygdalar neural ensemble that encodes the unpleasantness of pain. Science 363, 276–281 (2019). This study uses time-lapse in vivo calcium imaging in freely behaving mice to identify a distinct neural ensemble in the BLA that encodes the negative affective valence of pain and drives behavioural avoidance responses to noxious stimuli.
Yalcin, I. & Barrot, M. The anxiodepressive comorbidity in chronic pain. Curr. Opin. Anaesthesiol. 27, 520–527 (2014).
Lee, M. C., Wanigasekera, V. & Tracey, I. Imaging opioid analgesia in the human brain and its potential relevance for understanding opioid use in chronic pain. Neuropharmacology 84, 123–130 (2014).
Wang, D. et al. Functional divergence of delta and mu opioid receptor organization in CNS pain circuits. Neuron 98, 90–108.e5 (2018).
Birdsong, W. T. et al. Synapse-specific opioid modulation of thalamo-cortico-striatal circuits. eLife 8, e45146 (2019).
Wu, W. Y., Liu, C. Y., Tsai, M. L. & Yen, C. T. Nocifensive behavior-related laser heat-evoked component in the rostral agranular insular cortex revealed using morphine analgesia. Physiol. Behav. 154, 129–134 (2016).
Peng, K. et al. Morphine attenuates fNIRS signal associated with painful stimuli in the medial frontopolar cortex (medial BA 10). Front. Hum. Neurosci. 12, 394 (2018).
Oertel, B. G. et al. Differential opioid action on sensory and affective cerebral pain processing. Clin. Pharmacol. Ther. 83, 577–588 (2008).
Navratilova, E. et al. Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain. J. Neurosci. 35, 7264–7271 (2015). This study reports that endogenous opioidergic signalling in the ACC is required to activate dopaminergic signalling in the NAc, which underlies reward associated with pain relief, and that non-opioidergic pain-relieving treatments also engage opioidergic circuits in the ACC to achieve reduction in pain affect.
Gomtsian, L. et al. Morphine effects within the rodent anterior cingulate cortex and rostral ventromedial medulla reveal separable modulation of affective and sensory qualities of acute or chronic pain. Pain 159, 2512–2521 (2018).
Navratilova, E. et al. Selective modulation of tonic aversive qualities of neuropathic pain by morphine in the central nucleus of the amygdala requires endogenous opioid signaling in the anterior cingulate cortex. Pain 161, 609–618 (2020).
Bannister, K. et al. Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain. Pain 158, 2386–2395 (2017).
Zhao, M., Wang, J.-Y., Jia, H. & Tang, J.-S. µ- but not δ- and κ-opioid receptors in the ventrolateral orbital cortex mediate opioid-induced antiallodynia in a rat neuropathic pain model. Brain Res. 1076, 68–77 (2006).
Lee, M. C. et al. Amygdala activity contributes to the dissociative effect of cannabis on pain perception. Pain 154, 124–134 (2013).
Weizman, L. et al. Cannabis analgesia in chronic neuropathic pain is associated with altered brain connectivity. Neurology 91, e1285–e1294 (2018).
Kim, J., Farchione, T., Potter, A., Chen, Q. & Temple, R. Esketamine for treatment-resistant depression - first FDA-approved antidepressant in a new class. N. Engl. J. Med. 381, 1–4 (2019).
Pan, W. et al. Ketamine differentially restores diverse alterations of neuroligins in brain regions in a rat model of neuropathic pain-induced depression. Neuroreport 29, 863–869 (2018).
Tappe-Theodor, A. & Kuner, R. A common ground for pain and depression. Nat. Neurosci. 22, 1612–1614 (2019).
Hirschberg, S., Li, Y., Randall, A., Kremer, E. J. & Pickering, A. E. Functional dichotomy in spinal- vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats. eLife 6, e29808 (2017).
Lefaucheur, J. P. et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018). Clin. Neurophysiol. 131, 474–528 (2020).
Lamusuo, S. et al. Neurotransmitters behind pain relief with transcranial magnetic stimulation — positron emission tomography evidence for release of endogenous opioids. Eur. J. Pain 21, 1505–1515 (2017).
Borckardt, J. J. et al. Prefrontal versus motor cortex transcranial direct current stimulation (tDCS) effects on post-surgical opioid use. Brain Stimul. 10, 1096–1101 (2017).
Taylor, J. J., Borckardt, J. J. & George, M. S. Endogenous opioids mediate left dorsolateral prefrontal cortex rTMS-induced analgesia. Pain 153, 1219–1225 (2012).
Arendsen, L. J., Hugh-Jones, S. & Lloyd, D. M. Transcranial alternating current stimulation at alpha frequency reduces pain when the intensity of pain is uncertain. J. Pain 19, 807–818 (2018).
Ahn, S., Prim, J. H., Alexander, M. L., McCulloch, K. L. & Fröhlich, F. Identifying and engaging neuronal oscillations by transcranial alternating current stimulation in patients with chronic low back pain: a randomized, crossover, double-blind, sham-controlled pilot study. J. Pain 20, 277.e1–277.e11 (2019).
Pagano, R. L. et al. Motor cortex stimulation inhibits thalamic sensory neurons and enhances activity of PAG neurons: possible pathways for antinociception. Pain 153, 2359–2369 (2012).
Youssef, A. M., Macefield, V. G. & Henderson, L. A. Pain inhibits pain; human brainstem mechanisms. Neuroimage 124, 54–62 (2016).
McPhee, M. E. & Graven-Nielsen, T. Recurrent low back pain patients demonstrate facilitated pronociceptive mechanisms when in pain, and impaired antinociceptive mechanisms with and without pain. Pain 160, 2866–2876 (2019).
Moont, R., Crispel, Y., Lev, R., Pud, D. & Yarnitsky, D. Temporal changes in cortical activation during conditioned pain modulation (CPM), a LORETA study. Pain 152, 1469–1477 (2011).
Youssef, A. M., Macefield, V. G. & Henderson, L. A. Cortical influences on brainstem circuitry responsible for conditioned pain modulation in humans. Hum. Brain Mapp. 37, 2630–2644 (2016).
Zeidan, F. & Vago, D. R. Mindfulness meditation-based pain relief: a mechanistic account. Ann. N. Y. Acad. Sci. 1373, 114–127 (2016).
Zeidan, F. et al. Mindfulness-meditation-based pain relief is not mediated by endogenous opioids. J. Neurosci. 36, 3391–3397 (2016).
Eippert, F. et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63, 533–543 (2009).
Zeidan, F. et al. Mindfulness meditation-based pain relief employs different neural mechanisms than placebo and sham mindfulness meditation-induced analgesia. J. Neurosci. 35, 15307–15325 (2015).
Lui, F. et al. Neural bases of conditioned placebo analgesia. Pain 151, 816–824 (2010).
Zunhammer, M., Bingel, U. & Wager, T. D. Placebo effects on the neurologic pain signature: a meta-analysis of individual participant functional magnetic resonance imaging data. JAMA Neurol. 75, 1321–1330 (2018).
Bingel, U., Lorenz, J., Schoell, E., Weiller, C. & Büchel, C. Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain 120, 8–15 (2006).
Petrovic, P. et al. A prefrontal non-opioid mechanism in placebo analgesia. Pain 150, 59–65 (2010).
Zeng, Y. et al. A voxel-based analysis of neurobiological mechanisms in placebo analgesia in rats. Neuroimage 178, 602–612 (2018).
Kong, J. et al. Functional connectivity of the frontoparietal network predicts cognitive modulation of pain. Pain 154, 459–467 (2013).
Woo, C. W., Roy, M., Buhle, J. T. & Wager, T. D. Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain. PLoS Biol. 13, e1002036 (2015).
Segerdahl, A. R., Mezue, M., Okell, T. W., Farrar, J. T. & Tracey, I. The dorsal posterior insula subserves a fundamental role in human pain. Nat. Neurosci. 18, 499–500 (2015). This study uses an innovative approach to pinpoint the dorsal PI as being fundamental to nociception and pain.
Wiech, K., Jbabdi, S., Lin, C. S., Andersson, J. & Tracey, I. Differential structural and resting state connectivity between insular subdivisions and other pain-related brain regions. Pain 155, 2047–2055 (2014).
Lieberman, M. D. & Eisenberger, N. I. The dorsal anterior cingulate cortex is selective for pain: results from large-scale reverse inference. Proc. Natl Acad. Sci. USA 112, 15250–15255 (2015).
Davis, K. D., Bushnell, M. C., St Iannetti, G. D., Lawrence, K. & Coghill, R. Evidence against pain specificity in the dorsal posterior insula. F1000Res 4, 362 (2015).
Carrillo-Reid, L. & Yuste, R. Playing the piano with the cortex: role of neuronal ensembles and pattern completion in perception and behavior. Curr. Opin. Neurobiol. 64, 89–95 (2020).
Buzsaki, G. Neural syntax: cell assemblies, synapsembles, and readers. Neuron 68, 362–385 (2010).
Buzsaki, G. & Draguhn, A. Neuronal oscillations in cortical networks. Science 304, 1926–1929 (2004).
Doan, L., Manders, T. & Wang, J. Neuroplasticity underlying the comorbidity of pain and depression. Neural Plast. 2015, 504691 (2015).
Nees, F. & Becker, S. Psychological processes in chronic pain: influences of reward and fear learning as key mechanisms — behavioral evidence, neural circuits, and maladaptive changes. Neuroscience 387, 72–84 (2018).
Cai, Y. Q., Wang, W., Paulucci-Holthauzen, A. & Pan, Z. Z. Brain circuits mediating opposing effects on emotion and pain. J. Neurosci. 38, 6340–6349 (2018).
Zhou, W. et al. A neural circuit for comorbid depressive symptoms in chronic pain. Nat. Neurosci. 22, 1649–1658 (2019).
The authors thank all members of their laboratory as well as scientists in the Heidelberg Pain Consortium (CRC1158 of the Deutsche Forschungsgemeinschaft) for thought-provoking discussions and expert viewpoints. The authors acknowledge funding to R.K. from the Deutsche Forschungsgemeinschaft in the form of grants for Collaborative Research Centre 1158 (projects B01 and B06) and from the Baden-Württemberg Foundation (Internationale Spitzenforschung; BWST-ISF2017-069). L.L.T. was partially supported by a postdoctoral fellowship from the European Molecular Biology Organization. R.K. is a member of the Molecular Medicine Partnership Unit in the Medical Faculty in Heidelberg and the European Molecular Biology Laboratory.
Nature Reviews Neuroscience thanks Elizabeth May, who co-reviewed with Markus Ploner; Patrick Sheets; and Gregory Scherrer for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Multivariate pattern analysis
A set of tools that can analyse and identify neural responses in the brain as spatially distributed patterns of activity.
- Machine learning
The use of computer algorithms to learn, analyse, identify and predict patterns from data sets with minimal human supervision.
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Tan, L.L., Kuner, R. Neocortical circuits in pain and pain relief. Nat Rev Neurosci 22, 458–471 (2021). https://doi.org/10.1038/s41583-021-00468-2
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