Abstract
Pain is a multifaceted process that encompasses unpleasant sensory and emotional experiences. The essence of the pain process is aversion, or perceived negative emotion. Central sensitization plays a significant role in initiating and perpetuating of chronic pain. Melzack proposed the concept of the “pain matrix”, in which brain regions associated with pain form an interconnected network, rather than being controlled by a singular brain region. This review aims to investigate distinct brain regions involved in pain and their interconnections. In addition, it also sheds light on the reciprocal connectivity between the ascending and descending pathways that participate in pain modulation. We review the involvement of various brain areas during pain and focus on understanding the connections among them, which can contribute to a better understanding of pain mechanisms and provide opportunities for further research on therapies for improved pain management.
1 Introduction
Pain is a complex and multifactorial subjective experience, as defined by the International Association for the Study of Pain (IASP): “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.” (Raja et al. 2020) When pain persists or recurs for more than three months, it is categorized as chronic pain (Cavalcanti et al. 2021). Chronic pain often presents as a persistent and unavoidable stressor, leading to emotional changes that contribute to its aversive nature. Additionally, a reciprocal relationship exists between pain and affective states, where emotional experiences can exacerbate pain symptoms and perpetuate a vicious cycle between sensory and affective dimensions (Wiech and Tracey 2009). Based on anatomical, physiological, and psychological substrates, pain can be categorized into four main components: nociception, pain perception, suffering, and pain behaviors (Loeser and Melzack 1999). Moreover, there are three main types of pain: nociceptive, neuropathic, and nociplastic, as defined by the IASP (Cohen et al. 2021).
Furthermore, Melzack proposed the concept of the “pain matrix”, which emphasizes that the pain experience arises from the coordinated activity of various brain areas, rather than a single pain center (Melzack 1999). He suggested that the body’s anatomical foundation consists of a neuronal network that extends across extensive brain regions (neuromatrix), generating distinctive patterns of nerve impulses corresponding to different bodily sensations (Melzack 2001). These findings suggest that pain involves the collaborative engagement of interconnected brain structures, potentially encoding sensory and emotional experiences through specific neural pathways.
The “pain matrix” can be anatomically and functionally divided into medial and lateral ascending pathways (Figure 1) (De Ridder et al. 2021; May 2008, 2011; Peyron et al. 2000; Schnitzler and Ploner 2000). The lateral ascending pathway, composed of the thalamus, primary somatosensory cortex (S1), secondary somatosensory cortex (S2), and insular cortex (IC), primarily contributes to the sensory discriminative aspects of pain. Conversely, the medial ascending pathway is believed to process the affective dimensions of pain and encompasses the parabrachial nucleus (PB), prefrontal cortex (PFC), anterior cingulate cortex (ACC), and amygdala (AMG). Moreover, descending pathway, originating in the PFC, ACC, AMG, hypothalamus, and the periaqueductal gray (PAG), modulates nociceptive signal transmission by relaying signals through brainstem nuclei in the PAG and medulla that project to the spinal cord (Cohen and Mao 2014; Millan 2002; Zhuo and Gebhart 1997).
Anatomy of the pain neuromatrix. Peripheral nociceptive afferent information projects from the spinal dorsal horn to different targets in the brain. In the ascending pain modulation, the spinothalamic pathway projects to the somatosensory cortex and insula to participate in the sensory-discriminative aspects of pain, while the emotional-affective aspects of pain involve projections from the spino-parabrachio-amygdaloid to prefrontal cortex and limbic system. There is also descending pain modulation mediated by higher structure that project via the PAG to the RVM and finally efferent from the SDH. Abbreviations: SDH, spinal dorsal horn; PB, parabrachial nucleus; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; AMG, amygdala; PFC, prefrontal cortex; ACC, anterior cingulate cortex; PAG, periaqueductal gray; RVM, rostral ventromedial medulla.
It has been suggested that the imbalance between the ascending and descending pain modulation circuits is thought to be associated with chronic pain in pathological states (Apkarian et al. 2005; Apkarian et al. 2011). Thus, these results provide strong evidence supporting the notion that pain results from the interaction of ascending and descending pathways. And previous evidence has underscored the significance of central and peripheral sensitization in the initiation and maintenance of chronic pain. In this review, we focus on the pain matrix, explore the pain-related brain regions, and elucidate the neural mechanisms governing the ascending and descending pathways involved in pain regulation.
2 The lateral ascending pathway
The sensory discriminative aspects of pain encompass the perception of pain characteristics such as intensity, location, and quality, which are typically transmitted through the spinothalamic-cortical pathway, also known as the lateral pain pathway. Changes in the function of sensory afferent nerves can activate or deactivate the activity in the sensory discrimination dimension, consequently influencing pain processing (Hsieh et al. 2015; Ploner et al. 2000). In patients experiencing severe pain without depression, the plasticity of the pain neural network appears to be primarily confined to the sensory-discriminative aspects of pain (Joo et al. 2021). Furthermore, the abnormal processing of sensory information may also be related to aberrant connectivity from the somatosensory cortex to frontal cortex (Ren et al. 2019).
2.1 Thalamus
The thalamus, a global hub with extensive connections to the somatosensory cortex, transmits sensory information to the cortex and integrates information processing between cortical regions, and is widely recognized as a key region for pain transmission and regulation (Goadsby et al. 2017; Hwang et al. 2017; Lenz et al. 2004; Todd 2010). Approximately 35 % of the spinothalamic neurons terminate in the ventral posterior thalamic nucleus, projecting to S1 and S2, whereas about 25 % target the medial thalamus and then send their axons to the ACC and PFC (Kuner and Kuner 2021). Moreover, the connections between the mediodorsal thalamus (MD) and mPFC are likely to influence emotional and cognitive functions, whereas enhanced synaptic strength in the MD and ACC may contribute to the affective and motivational aspects of pain (Kong et al. 2018; Meda et al. 2019; Thompson and Neugebauer 2019).
One study demonstrated that cerebrovascular accidents in the ventral posterolateral thalamus can result in thermal hyperalgesia and mechanical allodynia, while another study suggested that the lateral thalamus plays a role in the processing of neuropathic pain, especially in thermal hyperalgesia (Nagasaka et al. 2017; Saadé et al. 2006). In line with this, the activation of GABAergic neurons in the ventrobasal thalamus or projections from the thalamic reticular nucleus to the ventrobasal thalamus has shown analgesia effects in chronic inflammatory pain (Zhang et al. 2017). A meta-analysis has indicated that the thalamus is active in both experimentally induced and chronic neuropathic pain conditions (Friebel et al. 2011). Moreover, recent studies have revealed a significant relationship between increased glutamate levels and decreased N-acetylaspartate levels in the thalamus and the development of mechanical allodynia induced by nerve injury, and the enhanced functional connectivity between the thalamus and insula contributes to the occurrence of neuropathic pain (Gustin et al. 2014; Wang et al. 2020).
Low-frequency oscillatory activity is a fundamental functional property of the brain and thalamus. It is noteworthy an early study has found that the abnormal distribution and coherence of thalamocortical low-frequency oscillations are related to the dysregulation of various chronic pain conditions (Llinás et al. 1999). Similarly, an fMRI study demonstrated the involvement of low-frequency oscillations in the thalamocortical network in ascending pain modulation and highlighted the role of abnormal connectivity within these networks in chronic neuropathic pain (Alshelh et al. 2016).
2.2 The primary somatosensory cortex (S1) and secondary somatosensory cortex (S2)
The S1 and S2 have been reported to contribute to the processing of nociceptive information, including the discrimination and localization of pain intensity (Bushnell et al. 1999; Chen et al. 2002). Activation of S1 and S2, as well as IC, has been associated with cold and thermal perception in the neocortex of mice (Beukema et al. 2018; Bokiniec et al. 2018). Furthermore, the involvement of S1 and S2 in the induction of relief from phantom limb pain has been confirmed using noninvasive brain stimulation techniques (Kikkert et al. 2019). A magnetoencephalography study has recorded a significant positive correlation between the intensity of pain stimulation and the activation of the contralateral S1 and bilateral S2 (Timmermann et al. 2001).
Several studies have proposed that various forms of abnormal plasticity in the S1 contribute to chronic pain. Notably, blocking S1 synaptic plasticity alone is insufficient to inhibit pain or even affect pain behavior following injury, indicating that the S1 may affect other pain-related regions that collectively result in chronic pain (Kim et al. 2016, 2017). A previous study demonstrated that optogenetic activation gamma oscillation in the S1 induced pain hypersensitivity and aversive avoidance behaviors, and S1 activity could also further lead to enhanced activation in downstream pain region such as the IC, ACC and AMG (Tan et al. 2019). However, the involvement of the S1 in pain-related negative emotions may not be independent but rather associated with its downstream brain regions. Chemogenic activation of S1 layer II/III neurons significantly reduced mechanical sensitivity and thermal latency (Okada et al. 2021). Interestingly, both excitatory and inhibitory neurons in the S1 layer II/III exhibited increased activity in chronic pain models, but the increase in inhibition was insufficient to counteract the increase in excitation and alleviate chronic pain (Eto et al. 2012).
The S2 is reported to be the final pathway responsible for integrating multimodal sensory information and facilitating the conversion of primary nociceptive signals from the periphery into acute pain perception (Worthen et al. 2011). A recent study discovered increased neural activity in the S2 in mice with spared nerve injury (Inami et al. 2019). Additionally, it has been reported that the S2 receives inputs from thalamic neurons, and a decrease in excitatory tone within the S2 was observed to modulate comorbid pain in depression, but not pain induced by inflammation or nerve injury (Zhu et al. 2019). However, the specific function of the S2 in pain processing requires further elucidation.
2.3 Insular cortex (IC)
The insular, located deep within the lateral fissure of the human brain, functions as a pivotal cortical hub and plays crucial roles in sensory processing, visceral responses, emotional guidance of social behavior, and perceptual self-awareness (Benarroch 2019; Craig 2003; Giesecke et al. 2004; Lu et al. 2016; Wang et al. 2021). Anatomically, the insula has different roles in pain processing: the posterior insular (PI) is primarily involved in the sensory-discriminative aspects of nociceptive inputs, whereas the anterior insular (AI) is more implicated in its affective dimensions (Craig 2002; Singer et al. 2009; Tracey 2005). Moreover, a recent study has shown that the diversity connectivity within the insular promotes to the division of insular functions to some extent (Tian and Zalesky 2018). The IC receives most of the spinothalamic inputs, and the PI and AI have distinct connections to the ascending spinothalamic pathways (Craig 2014; Dum et al. 2009).
Human electroencephalography studies have demonstrated that the IC is activated by acute or chronic pain states, and low-intensity electrical stimulation of the human IC can produce somatosensory sensations and visceral responses, further supporting the critical roles of the IC in pain and sensory perception (Mazzola et al. 2009; Ostrowsky et al. 2002; Ploghaus et al. 1999). Previous studies have found that excitatory patterns and changes are associated with the IC neuroplasticity after nerve injury (Ching et al. 2018; Han et al. 2016). Furthermore, peripheral nerve injury can active the IC and affect its the volume or thickness. A previous meta-analysis has shown that spinal cord injury can lead to volume loss in the gray matter in the IC, particularly in the left IC (Nardone et al. 2018; Wang et al. 2019).
The right AI has been reported to play an important role in large-scale switching, and this structure also contributes to neural networks disruption in chronic pain (Cottam et al. 2018). Additionally, recent study has revealed a relationship between the resting-state functional heterogeneity of the right IC and pain sensitivity (Veréb et al. 2021). Another study has suggested that morphological and functional network properties of the PI also participate in pain sensitivity (Neumann et al. 2021). Interestingly, a recent review found that neuropathic pain affects the AI more than the PI (Chao et al. 2018). Furthermore, the PI is also involved in the maintenance of persistent pain and contributes to the management of chronic pain (Benison et al. 2011; Segerdahl et al. 2015). These results indicate that distinct sites within the IC may be related to different aspects of pain processing.
3 The medial ascending pathways
The medial pain pathway, an essential neural circuitry involved in pain processing, encompasses a network of brain regions that contribute to the affective and emotional aspects of the pain experience. It is important to note that the affective components of pain are distinct from the sensory components, and addressing the affective aspects can further alleviate chronic pain (Zhou et al. 2018). The PB receives neural inputs from the superficial dorsal horn and projects diffusely to the limbic system, including the AMG and PFC, which are responsible for emotional processing. Overall, the spinal-parabrachial pathway may play a critical role in the emotional and autonomic components of pain. Further exploration and understanding of this pathway hold promise for advancing our comprehension of pain perception and developing potential therapeutic interventions.
3.1 Parabrachial nucleus (PB)
The PB, situated at the junction of the midbrain and pons, is widely recognized as a pivotal relay station responsible for receiving nociceptive information from the spinal cord and projecting it to the AMG and other brain regions, thereby converting sensory input into the emotional-affective components of pain. Efferent projections from PB neurons to the ventromedial hypothalamus (VMH) and PAG are responsible for mediating escape behavior, whereas projections to the bed nucleus stria terminalis (BNST) or AMG are involved in aversive learning to noxious stimulation (Chiang et al. 2020). Moreover, PB neurons that project to the thalamic paraventricular (PVT) induce negative emotion-related behaviors, without affecting nociceptive information processing (Zhu et al. 2022). Notably, Matusmoto et al. reported increased spontaneous and evoked activity of PB neurons in inflammatory pain models (Matsumoto et al. 1996), whereas hyperactivity of PB neurons in chronic trigeminal pain was observed solely in response to noxious thermal stimuli (Uddin et al. 2018). These finding underscore the crucial role of PB as a critical node in the pathogenesis of chronic pain and pain processing.
Through the use of single-cell RNA sequencing analysis, researchers identified 13 types of glutamatergic neurons and sparsely distributed GABAergic neurons within the PB, with the majority of PB neurons expressing multiple neuropeptides and receptors for Calcitonin gene-related peptide (CGRP) (Pauli et al. 2022). Inhibiting the PB has shown potential in attenuating chronic pain, with projections from GABAergic neurons in the central amygdala (CeA) to PB playing a major role as inhibitory inputs, thereby revealing that the activation of CeA-PB projections is involved in alleviating pain and negative affect-related behaviors (Hogri et al. 2022; Raver et al. 2020). Despite GABAergic neurons are scarce and dispersed in the PB compared to glutamatergic neurons, the activation of local GABAergic neurons in the PB is sufficient to achieve direct monosynaptic innervation and functionally inhibit glutamatergic neurons (Sun et al. 2020a). CGRP is encoded by Calca, a calcitonin-related mRNA splice variant, and the strong expression of μ-opioid receptors in the PB is predominantly co-localized with CGRP/Calca neurons (Huang et al. 2021; Rosenfeld et al. 1983). These studies suggest that opioid withdrawal may induce hyperactivity in CGRP/Calca neurons, potentially contributing to the experience of negative emotions associated with opioid withdrawal and opioid-induced respiratory depression.
3.2 Amygdala (AMG)
The AMG, an almond-shaped nuclear complex in the limbic system, was first proposed by Burdach in the early 19th century (LeDoux 2007). Given its well-established role in affective processing and recent findings demonstrating its involvement in nociceptive processing, the AMG is recognized as a unique site that influences pain modulation (Neugebauer et al. 2004; Veinante et al. 2013). Dysfunction of the AMG has been associated with an increased risk of chronic pain development, as decreased AMG volume and increased intra-corticolimbic white matter connections are independent risk factors for pain persistence (Vachon-Presseau et al. 2016). Recent studies on fear learning in humans and animals have consistently suggested that anxiety results from abnormalities in the mechanisms responsible for regulating conditioned fear (Pare and Duvarci 2012). Remarkably, AMG plasticity is believed to play a crucial role in emotion modulation, particularly in fear condition.
Multiple nuclei in the AMG participate in pain-related functions, including the central nucleus (CeA), the basolateral complex (BLA), and the intercalated cell clusters (ITC) (Sah et al. 2003; Thompson and Neugebauer 2017). The CeA, which is responsible for the primary function of AMG outputs, receives nociceptive inputs directly from PB via the spino-parabrachio-amygdaloid pathway and higher processed information inputs indirectly from the thalamus and cortex via the BLA (Neugebauer 2020). The two excitatory inputs from PB and BLA converge in CeA, where they integrate and regulate emotional responses. An optogenetic study has recently shown that activation of excitatory projections from PB to CeA induces negative emotional behaviors in rats, including aversion, anxiety, and depression, whereas the excitatory projections from BLA to CeA counteract these behaviors (Cai et al. 2018). Given that the BLA is a key site of convergence for negative and positive behavior, BLA-CeA projections also contribute to aversive behaviors such as anxiogenesis and defensive responses (Kim et al. 2016, 2017). Additionally, pain significantly increased the synaptic strength of PB inputs in the lateral division of CeA cells when receiving only PB inputs, while it selectively enhanced the synaptic strength of BLA inputs but not PB inputs when receiving both BLA and PB inputs (Ge et al. 2022). Exploring how AMG circuits, particularly those within the CeA, modulate behavioral responses to positive emotions (reward) and negative emotions (aversion, fear, and anxiety) would be of great interest.
The CeA neurons are functionally and neurochemically heterogeneous, consisting of distinct populations of GABAergic neurons that express a variety of neuropeptides, including CGRP, corticotropin releasing factor (CRF), protein kinase C-delta (PKCδ), and somatostatin (SOM) (Neugebauer et al. 2020). These distinct neuronal populations regulate various behaviors, such as anxiety, depression and fear. Notably, blocking the CeA-CGRP receptor (Shinohara et al. 2017) and optogenetically inhibiting CeA-CRF neuron (Mazzitelli et al. 2021, 2022) have demonstrated the potential to alleviate pain and emotional-affective responses. It has been shown that CGRP1 receptor blockade reduces CeA-CRF neuronal activity in chronic neuropathic pain, and that the reduction in CeA-CRF neuronal activity is critical for the facilitated behavioral responses observed with CGRP1 receptor antagonism (Presto and Neugebauer 2022). Recent studies have been shown that activation of CeA-PKC-δ neurons increases anxiolytic effects in mice (Cai et al. 2014; Griessner et al. 2021), whereas activation of CeA-SOM neurons induces the appearance of anxiety-like behaviors (Ahrens et al. 2018). In contrast, Wilson et al. identified that activation of CeA-SOM neurons contributed to pain relief, whereas increased activity of CeA-PKCδ neurons amplified pain-related behaviors, and that both of the two distinct neurons were recipients of inputs from PB (Wilson et al. 2019). An agent-based model has demonstrated that the relative proportion of PKCδ and SOM neurons is a key parameter in predicting pain and this parameter exhibits significant left-right lateralization (Miller Neilan et al. 2021). Interestingly, studies on the hemispheric lateralization of pain-related amygdala function have suggested that the right CeA plays a predominant role in facilitating pain-related behavior, compared with the left CeA (Allen et al. 2021; Sadler et al. 2017).
3.3 Prefrontal cortex (PFC)
Growing evidence from rodent and human studies has confirmed that the PFC plays a critical role in integrating sensory, cognitive, and emotional information related to pain experiences (Bushnell et al. 2013; Hashmi et al. 2013; Maihöfner and Handwerker 2005; Seminowicz and Moayedi 2017). Meanwhile, numerous neuroimaging studies have focused on functional localization and subdivision of the human PFC, suggesting its constituents as the medial PFC (mPFC), dorsolateral PFC (dlPFC), ventrolateral PFC, and orbitofrontal cortex (OFC) (Carlén 2017). Notably, the subregion that is related to pain is localized in the mPFC (Apkarian et al. 2011). The mPFC consolidates pain-related sensory characteristics and affective information, evaluates motivational factors, and computes action progress through motor circuits, to relieve or aggravate pain. Nerve injury results in significant alterations tactile stimuli processing in the ventral mPFC and indicates that ERK phosphorylation participates in pain perception, particularly in neurons located in layers II–III and V–VI (Devoize et al. 2011). Similarly, dysregulation of glutamatergic inputs in neuropathic pain may result in mPFC inactivation and potentially impair PFC-dependent cognitive tasks (Kelly and Martina 2018). Neurophysiological recordings of the mPFC and the mediodorsal thalamus connectivity are relevant to deficits in pain-related working memory (Cardoso-Cruz et al. 2013). According to anatomical and physiological function, the mPFC in rodent consists of the anterior cingulate cortex (ACC), the prelimbic cortex (PL), and the infralimbic cortex (IL) (Laubach et al. 2018).
3.3.1 The anterior cingulate cortex (ACC)
There is converging evidence demonstrating that ACC is critically important for the sensory perception and emotional responses (Barthas et al. 2015; Bushnell et al. 2013; Fuchs et al. 2014; Johansen and Fields 2004; Sellmeijer et al. 2018). Mediodorsal thalamic projections to ACC are involved in chronic pain-related aversion by inhibiting subcortically projecting ACC neurons, whereas BLA-ACC input mitigates aversion (Meda et al. 2019). Additionally, transplanting medial ganglionic eminence cells to the rostral ACC enhances GABAergic inhibitory control and alleviates long-lasting pain-induced aversiveness, but not in the posterior ACC (Juarez-Salinas et al. 2019). Optogenetic activation of the ACC-spinal cord pathway is involved in neuropathic pain hypersensitivity behaviors, whereas its inhibition induces analgesic effects, and the modulation of this pathway is independent of RVM (Chen et al. 2018).
Chronic pain-induced long-lasting anxiety is known to depend on presynaptic plasticity. Early study has demonstrated that long-term potentiation (LTP) of synaptic transmission in the ACC could result in exaggerated chronic pain responses (Li et al. 2010). Blocking hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the ACC to erase presynaptic LTP has been shown to significantly reduce anxiety-like behaviors induced by chronic pain (Koga et al. 2015). Another study reported that in neuropathic pain, abnormal HCN channel function of cortical output neurons in the ACC layer V could be restored by type 7 serotonin receptors (5-HT7) (Santello and Nevian 2015). Furthermore, downregulation of mGluR1 has been shown to alleviate the neuronal hyperexcitability of layer V pyramidal neurons in the ACC, which is inhibited by HCN channels (Gao et al. 2016).
A long-standing hypothesis suggests that females may exhibit heightened sensitivity to pain and associated unpleasant emotions compared to males (Pieretti et al. 2016). Evidence suggests that sex differences in excitatory glutamatergic neurons within the ACC play a crucial role in the sensory and affective aspects of pain (Jarrin et al. 2020). Several studies have suggested that women with chronic pain exhibit aberrant ACC circuitry compared to men (Monroe et al. 2018; Osborne et al. 2021). Similarly, neuroimaging data has also identified sex differences in the functional and structural connectivity between the ACC and the descending antinociceptive pathway (Wang et al. 2014). These findings suggest that female brain circuits are more extensively involved in the pain modulatory systems that mediate the habituation of pain.
3.3.2 The prelimbic and infralimbic (PL/IL)
More recently, a comparison of PL and IL projections in rodents and humans found that PL and IL are distributed very differently in the brain. Specifically, the PL primarily projects to limbic system, which is involved in cognition-related function, whereas the IL projects to autonomic/visceral-related sites that affect visceromotor activity (Vertes 2004, 2006). Importantly, complicated goal-directed behaviors require the integration of cognitive and visceromotor activities, which involves the interactions between PL and IL. It has been demonstrated that there is a direct reciprocal layer V–VI connection in PL and IL, and this connection is essential for new learning and fear extinction (Marek et al. 2018; Mukherjee and Caroni 2019).
The PL is located in the medial wall of the PFC in rodents, and consolidates action-outcome relationships and affects action-outcome-driven behavior (Autry and Monteggia 2012; Woon et al. 2020). A recent study found that inactivation of the PL, but not the IL, impairs the acquisition and expression of conditioned place avoidance, indicating that the PL contributes to the aversion dimension of pain and environmental context (Jiang et al. 2014). Optogenetic activation of PL excitatory neurons can attenuate thermal hyperalgesia and anxiety-like behavior in a chronic inflammatory pain model (Wang et al. 2015), while selective silencing of PL excitatory neurons reverses pain-related working memory deficits (Cardoso-Cruz et al. 2019). Furthermore, increasing the basal firing of neurons in the PL with low-frequency optogenetic stimulation scaled up prefrontal control and inhibited pain (Dale et al. 2018). Another study shows that the PL is capable of modulating both sensory and emotional responses to neuropathic pain, which is mediated by GABAergic inputs (Zhang et al. 2015). Interestingly, nerve injury increases the excitability of layer V parvalbumin-positive inhibitory neurons in the PL, consequently leading to a decrease in the excitability of layer V pyramidal neurons, with this effect observed exclusively in male mice and not in females (Jones and Sheets 2020).
Under inflammatory pain conditions, the deactivation of PL cortex cells has been associated with reduced levels of glutamate (and conversely increased GABA) in the PL/IL cortex (Luongo et al. 2013) Overexpression of mGluR1, but not mGluR5, has been recorded in the PL-IL in inflammatory pain, indicating that mGluR1 is involved in the connection between BLA and PL-IL neurons under inflammatory pain (Kelly et al. 2016; Luongo et al. 2013). Another study suggested that the IL cortex facilitates nociceptive behavior through a descending pathway via mGluR5 signaling in normal and arthritic rats, whereas mGluR1 activation is effective only in arthritic rats (David-Pereira et al. 2016; David-Pereira et al. 2017). Furthermore, rescuing impaired endocannabinoid signaling in the mPFC activates mGluR5 function to restore IL outputs, thereby inhibiting pain and attenuating pain-related cognitive function, whereas mGluR1 can reverse the inhibition of neuronal spontaneous firing and overcome pain-related cognitive deficits (Kiritoshi et al. 2016).
Optogenetic inhibition of the IL cortex has been shown to alleviate anxiety-like behavior, while the distinct IL outputs, including the lateral septum and the CeA, exert antagonistic effects in the modulation of anxiety (Chen et al. 2021). Knockdown of mTOR in the IL led to robust depression-like behaviors, accompanied by decreased expression of BDNF bilaterally in both the PL and IL (Garro-Martínez et al. 2021). It has also been reported that peripheral inflammation decreases BDNF levels in the IL, while supplementing BDNF in the IL has been found to alleviate pain and accelerate recovery from inflammatory pain (Yue et al. 2017).
4 The descending pain modulation
The establishment and maintenance of chronic pain involves the alterations in pain modulation pathways. The process of afferent somatosensory information is altered by pathways that descend from the brain to the spinal dorsal horn (SDH), thereby altering the perception and response to somatosensory stimuli and resulting in pain changes. Previous studies have elucidated the integration of descending inhibition and facilitation in the transmission of nociceptive information. The descending facilitation pathway is usually not significantly involved in nociception under normal conditions. Thus, it would be a valuable research hotspot in chronic pain, as it aims to restore the balance between the two pathways by reducing descending facilitation and enhancing the descending inhibition (Kwon et al. 2014). The descending pain modulation system also provides a mechanism for pain can be modulated in cortical and subcortical regions (Bourne et al. 2014). Many complex neural circuits in the brain are involved in the descending pathway, and the PAG-RVM-SDH pathway is considered the most important and classical neural pathway of the descending pain system (François et al. 2017; Heinricher et al. 2009; Lau and Vaughan 2014; Millan 2002; Ossipov et al. 2010).
4.1 Periaqueductal gray (PAG)
The midbrain PAG, an evolutionarily conserved region, plays significant roles in pain, anxiety, depression, and fear (Lau and Vaughan 2014; Tovote et al. 2016). Studies have demonstrated that the ventrolateral PAG (vlPAG) is an important part of the neural circuits that mediate pain regulation and serve as the primary site of endogenous opioid analgesia, and electrical stimulation of the vlPAG could produce a potent analgesic effect, while the dorsolateral/lateral PAG (dl/lPAG) prompts active defensive responses, such as jumping and running (Lanius et al. 2018; McPherson and Ingram 2022). A previous study has confirmed that the vlPAG comprises distinct subpopulations of neurons that modulate pain transmission. For example, persistent inflammation increases presynaptic GABA release from vlPAG neurons in female rats induced by CFA injection (Tonsfeldt et al. 2016). It has been shown that the activation of vlPAG glutamatergic neurons, in contrast to vlPAG GABA neurons, exerts analgesic and anxiogenic effects (Samineni et al. 2017; Zhu et al. 2019). Another study suggested that selective stimulation of dopaminergic neurons within the vlPAG/dorsal raphe produces antinociception without anxiogenic behavioral effects (Taylor et al. 2019).
Interestingly, in neuropathic pain, the activation of the mPFC/vlPAG pathway has a descending inhibitory effect (exerts analgesic and anxiolytic effects) and enhances the activity of GABAergic neurons in this region, while silencing the mPFC/vlPAG pathway may contribute to the establishment of pain and the emergence of anxiety-like behaviors (Yin et al. 2020). A previous study has suggested that nerve injury increases GABAergic interneuron inputs from the BLA to the mPFC due to the reduction in endocannabinoid regulation (Huang et al. 2019). These enhanced synaptic connections mediate projections in the mPFC/vlPAG, which contribute to hyperalgesia after peripheral nerve injury. Furthermore, Liang et al. proposed a novel neural pathway in which the activation of glutamatergic neurons in the posterior PVT-CeA-vlPAG pathway contributes to descending pain facilitation (Liang et al. 2020). Moreover, the activation of glutamatergic neurons projecting from the ACC to vlPAG also induces hyperalgesia and anxiety-like behaviors in nerve-injured mice (Zhu et al. 2021).
Output projections are another important target for investigation and can help us understand how different types of vlPAG neurons transmit to downstream targets and how they change in pathological states. The vlPAG-RVM pathway is widely recognized as the primary control pathway for effectively modulating spinal nociceptive processing. Additionally, other projection regions may also contribute to anti-nociception, thereby expanding our understanding of PAG subpopulations in the descending pathway. Recent studies have focused on dopaminergic neurons from the vlPAG to BNST promoting anti-nociception, and interestingly, the BNST GABAergic neurons that project to the vlPAG is implicated in feeding behavior (Hao et al. 2019; Yu et al. 2021). In addition, projections to the central medial thalamic nucleus may also participate in the transmission and regulation of neuropathic pain (Sun et al. 2020b).
4.2 Rostral ventromedial medulla (RVM)
The RVM acts as a relay station in the descending pathway, receiving descending projections from PAG, thalamus, PB and other encephalic regions, and subsequently projecting to the SDH, thereby playing a key role in the modulation of pain transmission in the central nervous system (Millan 2002; Tang et al. 2021). Based on their physiological characteristics and roles in pain regulation, RVM neurons are classified into three types: on-cell, off-cell, and neutral-cell (Bagley and Ingram 2020; Chen and Heinricher 2022; Heinricher et al. 2009; Ossipov et al. 2014). Electrophysiological studies in rodents have identified that on-cell and off-cell activities are responsible for the pronociceptive and antinociceptive outputs of the RVM, respectively (Heinricher et al. 1994; Heinricher et al. 2009; Morgan and Fields 1994). On-cell activity results in enhanced nociception, and selective activation of on-cell is sufficient to induce hyperalgesia, conversely, selective blockade of on-cell activity can prevent hyperalgesia (Martenson et al. 2009; Neubert et al. 2004). The imbalance between the outputs of the on-cell and off-cell populations can amplify or suppress nociception and pain behaviors. Similarly, mu-opioid receptor agonists can directly inhibit on-cell activity in the RVM and remove the inhibitory effect on off-cell, thereby inhibiting nociceptive transmission in the SDH (Fields 2000; Heinricher et al. 2009). Neutral-cells have showed almost no nociceptive responses, as shown by the absence of alterations in firing patterns during nociceptive reflexes, and it remains an open question whether neutral-cells have a role in pain modulation.
A recent study has shown that the RVM is activated 30 min after exposure to noxious stimuli, suggesting that the PAG-RVM pathway is involved in the early development of pain (Tobaldini et al. 2019). Consistently, the analgesic effect of sciatic nerve stimulation, which activates the RVM, takes effect on post-injury day 1 in a neuropathic pain model (Wong et al. 2022). It is well known that RVM-SDH descending pain modulation pathway releases either serotonin or the inhibitory neurotransmitters GABA and/or glycine. An optogenetic study has shown that activation and inhibition of RVM-SDH GABAergic neurons facilitate and attenuate mechanical pain, respectively, providing evidence that altering the activity of inhibitory RVM inputs into the SDH can achieve bidirectional control (François et al. 2017). Additionally, a previous study found that stimulation of RVM-SDH is inhibitory via GABAergic and glycinergic neurotransmission (no excitatory or serotonergic currents), and kappa-opioid receptor agonists inhibited the GABA/glycine terminals of RVM projections to the SDH, resulting in analgesic effects (Otsu and Aubrey 2022). Interestingly, kappa-opioid receptor agonists appear to exert pronociceptive effects on kappa-opioid receptor-containing RVM neurons that project to the SDH (Nguyen et al. 2022). These findings suggest that descending pain modulation can be considered as a key mechanism for opioid-induced analgesia, providing an opportunity for the endogenous opioid system to regulate pain.
5 Pain pathway is a complex neural network across various brain regions and processes
Pain is a complex experience that engages a network of brain regions, collectively known as the pain matrix, which are responsible for the integration of sensory, emotional, and cognitive processes. Two primary neural circuits contribute to pain processing: the ascending pain pathway and the descending pain pathway. The ascending pathway conveys nociceptive information from the peripheral to higher brain regions, while the descending pathway modulates nociceptive signals as they ascend. It is crucial to recognize that the pain pathway is not a linear, simplistic route, but rather a complex neural network with numerous connections across various brain regions and processes. Pain is not controlled by a single brain region alone, nor is a single brain region responsible for encoding only one aspect of pain. Instead, pain perception and processing involve complex interactions between various brain regions and neural pathways.
It is noteworthy that the thalamus receives nociceptive information from the brainstem and transmits pain signals to the somatosensory cortex and insular, thereby contributing to the perception of pain, including its location, intensity, and quality. Optogenetic inhibition of the S1/ACC pathway has been demonstrated to effectively alleviate pain-related affective symptoms (Singh et al. 2020). Furthermore, the IC is reciprocally connected with the S2, AMG, and ACC, and it has been suggested to play a crucial role in pain processing, particularly in pain intensity coding (Coghill et al. 1999). A recent review indicated that the functional connectivity between the IC and the S1/S2 cortex is significantly reduced in neuropathic pain (Yalcin et al. 2014). Additionally, other findings demonstrated that the IC-BLA pathway modulates both the somatosensory and aversive components of pain, while the MD-BLA pathway is only involved in modulating the aversive aspect of pain (Meng et al. 2022). Consistently, studies have suggested that the IC-BLA pathway is closely associated with the onset and development of empathic pain (Zhang et al. 2022). Furthermore, the ACC is functionally connected to the anterior insular and enables the integration of sensory input into motor, motivational, and emotional responses by switching between large-scale networks to facilitate attention access (Galhardoni et al. 2019).
Additionally, nociceptive information related to the emotional and cognitive aspects of pain ascends via the spino-parabrachio-amygdaloid pathway to the prefrontal cortex and limbic system. Previous studies have suggested that projections from the PB-CeA pathway participate in the nociceptive-emotional connection and it’s tightening in chronic pain (Kato et al. 2018). However, recent research has shown that the CeA-PB pathway efficiently modulates PB responses to nociceptive inputs, and dysregulation of this inhibition amplifies PB neuronal activity, contributing to the pathogenesis of chronic pain (Raver et al. 2020). Meanwhile, activation of AMG-PB projections reduces behaviors associated with negative emotions and enhances behaviors associated with positive effects (Hogri et al. 2022). Subsequent investigations have revealed that the PB projects directly to the IC and IL/PL, which are responsible for visceral sensory and motor cortical areas, respectively (Chiang et al. 2019; Saper and Loewy 2016). Individuals with chronic low back pain exhibit greater resting-state functional connectivity and lower effective connectivity of the AMG-mPFC pathway (Mao et al. 2022). Previous research has demonstrated that in a rat model of arthritis pain, hyperactivity of BLA neurons results not only in the emotional-affective components of pain but also in pain-related decision-making impairments through BLA-mPFC connectivity (Ji et al. 2010). The ACC-BLA circuit has been reported to play a critical role in fear response (Allsop et al. 2018; Jhang et al. 2018). Furthermore, previous studies have demonstrated that the targeting of the PL and IL cortex by the BLA has differential implications for fear conditioning within mPFC networks, whereby BLA inputs to IL may enhance extinction while BLA inputs to PL may facilitate fear expression (Jhang et al. 2018; Senn et al. 2014). Interestingly, another study showed that projection from IL, but not PL, to the BLA was sufficient to attenuate anxiety-like behaviors (Bloodgood et al. 2018; Chen et al. 2021).
The descending pain modulation pathway, also known as the antinociceptive pathway, affects the transmission of information in the brain through the activation of the on or off cells. Moreover, the descending pathway is capable of releasing endogenous opioids, which play an important role in the endogenous modulation of nociceptive transmission in the central nervous system. The PAG serves as a pivotal relay station that integrates sensory and motor functions by receiving inputs from higher centers, such as the AMG, PFC, and ACC, and projecting to the RVM, which ultimately targets the SDH to control the transmission of nociceptive signal (Donaldson and Lumb 2017; Koutsikou et al. 2015). The descend pathway enables the brain to exert top-down control over pain perception. Previous studies have shown that increased ACC projections to the dl/lPAG modulate reflexive and active avoidance behaviors to pain, whereas decreased inputs from the PL to vlPAG are critical for the development and progression of chronic pain (Drake et al. 2021; Lee et al. 2022). These findings suggest that the projections from the PL and ACC to different subregions of PAG exert opposing effects on pain and defensive behavior. Furthermore, the ACC-PAG-RVM pathway appears to contribute to placebo analgesia, which involves the endogenous opioid system (Eippert et al. 2009; Fields 2004). Furthermore, the BLA-mPFC-PAG pathway is involved in the development of mechanical and thermal hypersensitivity responses after peripheral nerve injury, whereas the PFC-AMG-PAG pathway is shown to mediate fear-conditioned analgesia (Butler et al. 2011; Huang et al. 2019).
Notably, the PAG not only receives direct inputs from the spinomesencephalic tract but also receives ascending inputs from the superficial and deep dorsal horns through the PB, contributing to nociception, analgesia, and aversive behaviors (Roeder et al. 2016; Willis and Westlund 1997). Moerover, the PAG transmits signals to forebrain sites via t he PB to modulate ascending nociceptive and/or visceral information (Krout et al. 1998). Interestingly, vPAG-CeA projections are modulated by serotonin and are involved in the response to fear learning (Hon et al. 2022). Overall, the processing of pain involves a complex network of brain regions and pathways, which work together to perform pain perception, assessment, and regulation to allow the body to be protected and respond appropriately when faced with painful stimuli.
6 Conclusions
Multiple brain regions are involved in the establishment and maintenance of chronic pain. Indeed, the persistence of chronic pain in the brain can lead to changes in brain areas involved in emotion and cognition, resulting in symptoms such as depression, anxiety, memory impairment. Central and peripheral sensitization, as well as alterations in pain modulation pathways, is typically associated with chronic pain. Thus, the overall experience of pain is the result of a collection of network activity generated by distinct regions in the brain together with ascending and descending pathways.
This review provides an in-depth analysis of the functional connectivity between various brain regions associated with pain, revealing the nociceptive and affective networks related to pain perception. Pain is mediated by at least two ascending excitatory pathway and one descending pain modulation pathway (De Ridder and Vanneste 2017). The medial and lateral ascending pain pathways function simultaneously and can be modulated individually without interfering with other pathways, although they typically work together (Bushnell et al. 2013; Frot et al. 2008). The cerebral cortex receives ascending nociceptive inputs from the SDH and subsequently projects them to distinct brain regions involved in pain regulation, which is essential for the control of pain threshold and its emotional components.
In recent years, brain functional imaging techniques have been employed to study the mechanisms of chronic pain, providing profound insight into changes in pain matrix during pain processing (Frøkjær et al. 2018; Morton et al. 2016). With the maturity of optogenetics and chemogenetics techniques, as well as the emerging single-cell transcriptomic and epigenomic technologies, we now have the possibility to further investigate pain-related neural circuits and cell-targeted therapy in specific brain regions. Pain management remains to be a huge challenge, and only by thoroughly understanding its mechanisms and investigating innovative therapeutic targets and treatment can we alleviate discomfort and improve the well-being of patients. Therefore, we look forward to developing more effective pain management programs based on the pathophysiology of pain through multidisciplinary collaboration in the future.
Funding source: Zhejiang Provincial Department of Medicine and Health Science and Technology
Award Identifier / Grant number: No. YH42021010
Funding source: National Natural Science Foundation of China
Award Identifier / Grant number: No.82001424
Award Identifier / Grant number: No.82171176
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Author contributions: Gang Chen had the idea for the article; Dandan Yao and Yeru Chen drafted the manuscript. All authors read and approved the final manuscript.
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Research funding: This research was supported by the National Natural Science Foundation of China (No.82171176 and No.82001424), and the Zhejiang Provincial Department of Medicine and Health Science and Technology (No. YH42021010).
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Conflict of interests: The authors declare no competing interests.
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