The medial STT is often referred to as the “paleospinothalamic” tract in the earlier literature. Neurons projecting to medial STT have larger receptive fields and are thought to be involved in the motivational-affective aspects of pain [16, 52, 67]. Medial STT cells are more likely in deeper dorsal horn and ventral horn [90] and projects to medial and intralaminar nuclei of thalamus [4, 10, 54]. This tract has no somatotopic organization [10, 45], is thought to carry less localized, burning or dull pain [45, 95], and to contribute to aversive motivation and other non-discriminative aspects of pain [10, 21, 54, 95]. Medial STT has some diffusion along the way to reticular formation in brainstem [16, 45, 95] before ending in the medial and intralaminar thalamic nuclei [16, 45].
Spinoreticular tract (SRT)
Spinoreticular tract (SRT) neurons are predominantly located in lamina VII and VIII in the ventral horn [16, 52, 56, 81, 90, 95], perhaps also in lamina I [81, 90, 95], V [81, 95], VI [16, 81] and nucleus proprius (lamina IV) [87]. SRT projects ipsi-, contra-, and bi-lateral nociceptive inputs [16, 52, 87], however the majority of the spinoreticular fibers ascend ipsilaterally [87] along with the STT and SMT in the anterolateral spinal cord [16, 90].
Termination occurs on several nuclei of medullary and pontine reticular formation [52, 87], perhaps most prominently in rostroventral medulla (RVM), including nucleus gigantocellularis [10, 16, 31, 81, 83, 87, 90], nucleus paragigantocellularis [87] [90], and nucleus raphe magnus (NRM) [87]. Collaterals also terminate among almost all catecholamine cell groups of medulla and pons, including A5 and A7 and cell groups locus ceruleus (A6) [81, 90]. There seems to be no obvious somatotopic organization [90]. The primary functional significance of SRT seems to be to signal homeostatic changes to brainstem autonomic centers, activation of endogenous analgesia, and relay of information to trigger motivational-affective responses [16, 90].
Central sensitization
Central hypersensitivity can be caused by activation of nociceptive fibers, ectopic or normal [2]. Changes in spinal cord response to innocuous and nociceptive stimuli have been observed in states of both acute and prolonged inflammation [70]. Several mechanisms have been identified in relation to central sensitization and hypersensitivity:
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Lower discharge threshold of spinal cord neurons – discharging in response to stimuli so weak that they would normally not elicit a pain response [2, 52, 70]
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Spontaneous discharge of nociceptors and neurons involved in nociceptive processing – under normal conditions the spontaneous discharge is never at frequencies seen in response to nociceptive stimuli under healthy conditions [2, 55]. High spontaneous discharge has been noted in thalamus neurons following nervous system lesions [2]
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Increased frequency of spinal cord neurons – firing frequency more than directly proportional to input intensity, a phenomenon known as wind-up [2, 54, 56]
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Broadening of the receptive field of spinal cord neurons – also referred to as secondary hyperalgesia or allodynia [2, 52, 56, 70, 93, 94]
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Posthumous discharge of spinal cord neurons – the neurons continue to discharge even after stimulation [2]
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Reduced central inhibitory system – reduction in number of inhibitory transmitters, down-regulation of receptors, interruption of descending pathways, and/or loss of inhibitory interneurons [2, 54]
The C-fiber nociceptors release glutamate as neurotransmitter and spinal cord neurons receiving their input express glutaminergic receptors such as NMDA and AMPA. Glutamate primarily acts on NMDA (but to certain extent also AMPA) [9]. Central sensitization has been associated with NMDA-type receptors [36, 54, 93]. Wind-up, the state of increased membrane excitability in the dorsal horn neurons mentioned above, is a phenomenon resulting from repeated input from nociceptors and is mediated by NMDA-receptors on spinal neurons [27, 36, 52]. This occurs for all types of C-fibers input, normal input from uninjured tissue also produces small and fleeting sensitization, but large and prolonged input produces more prominent and long-lasting central sensitization [9]. Just a few seconds of low-frequency C-fiber input can lead to several minutes of postsynaptic depolarization [52]. This process may be modelled by differential equations that describe the temporal evolution of the concentration of chemicals in and around neurons following stimulation [3].
Nerve damage can lead to recruitment of novel inputs, specifically from Aβ-fibers which signal innocuous touch. This occurs through altered central processing [7, 52, 55]. New and possibly abnormal circuits can form by sprouting of Aβ-fibers into lamina II [7, 54]. In neural network models this process may be modelled as some form of activation-dependent plasticity.
Perception
The role of cortical areas in pain perception was eloquently expressed by Wolf in 1967 [92]:
Because of these multifarious associations for pain in the interpretive areas of cortex, pain is no more a simple perception of a sensory experience than insult is a simple perception of a sound
There is no single region of the brain that is solely responsible for pain perception, in fact, pain involves a wide range of different cortical and subcortical structures. Figure 7 displays some of the most mentioned brain regions in connection to pain perception.
Due to the high level of interconnectivity and complexity, and the yet rather limited experimental evidence for the exact role of individual brain regions in pain processing, it is likely difficult to build a mathematical model that encompasses all the relevant regions while also providing informative insight into the underlying mechanisms. Neural network models may be informative about dynamics and plasticity within and between certain cortical and subcortical regions [14]. Another possible alternative to modelling supraspinal pain processing is to consider a higher level of abstraction: cognitive computational neuroscience. While these types of models generally are not rooted in neurophysiology, they can still provide insight into how information is integrated and processed at the cognitive level and ultimately influence the experience of pain. Examples of models in this domain are Bayesian inference models, reinforcement learning and Kalman filters [5, 50, 73, 86].
Thalamus
Thalamus is a major relay point for sensory information [17, 79]. The STT projects primarily to contralateral sensory thalamus, i.e., the ventroposterior nucleus [69]. More specifically the lateral STT ends in ventral posterolateral nucleus (VPL) of thalamus [56, 79]. The VPL is topographically arranged so that the caudal part of body is located dorsolaterally and the head region ventromedially [74, 79, 95]. This nucleus also receives input from tactile and position senses from the contralateral side [95]. The VPL is thought to be involved in discriminative aspects of pain, due to the direct spinothalamic projections [10] with small receptive fields, graded response to stimulus intensity, and somatotopic organization [16, 46, 55]. Third-order neurons project their axons to primary somatosensory cortex (SI) [56, 87, 95] where the somatotopic organization is preserved, and to secondary somatosensory cortex (SII) [87]. There are also corticothalamic projections back to VPL [35, 79], which follow the same topographic pattern as thalamocortical projections [79]. Thalamus also receive input from other deep areas of the brain [35].
Some nociceptive fibers end in the intralaminar [4, 55, 79] and medial thalamic nuclei [4, 55]. They receive input from medial STT fibers and from the reticular formation [10, 87]. These nuclei respond to both noxious and innocuous stimuli applied to wide areas of the body and have no somatotopic organization [10, 55]. Lesions to this region are effective in relieving the affective dimension of pain but preserve somatosensory discrimination [10]. Intralaminar nuclei have widespread connections to cerebral cortex and various subcortical nuclei [95]. Intralaminar processes ending in insula are thought to be involved in dull or deep pain and the longer lasting emotional features of pain [51]. Medial dorsal nucleus is connected to prefrontal cortex (PFC) and the limbic system and is thought to be related to the arousal mechanism of pain [95].
Primary somatosensory cortex (SI)
All cutaneous sensations, such as temperature, touch, and pain are equally relayed to SI [74]. Imaging studies have shown convergent results that SI activation correlates with intensity of pain sensation [36, 63, 71, 81], but not pain unpleasantness. It has also been observed that SI plays a role in sensory-discriminative functions such as spatial discrimination and intensity encoding [36, 71, 81]. This is consistent with hypotheses that parietal cortex is essential for finer discrimination, localization, and determination of intensity [17, 79] based on observations of somatotopic organization of cerebral response along central sulcus [71].
Third-order neurons in the thalamus project to somatosensory cortex. Worthy of notice is evidence suggesting that SI is not essential for pain perception [10]. Findings supporting this idea are reports that electrical stimulation of somatosensory cortex can produce sensations of tingling, numbness or electricity, but rarely pain [21, 55], and that lesions to these areas are not always sufficient to entirely alleviate pain [21, 55, 71].
Secondary somatosensory cortex (SII)
The secondary somatosensory cortex (SII) may play a role in tactile object recognition and also recognition of the nature of noxious stimuli [71]. SII projects via insula to temporal lobe limbic structures. These corticolimbic structures are proposed to subserve tactile learning and memory. Anatomic studies indicate that SII receives projections from lateral thalamic nuclei, mainly ventral posterior inferior thalamic nuclei (VPI) [71, 81], but also the ventral posteromedial nucleus [16] and VPL [16, 56], and from SI [16]. Neurons mostly have large bilateral receptive fields, and encode intensity poorly [71].
Anterior cingulate cortex (ACC)
The anterior cingulate cortex (ACC) is thought to be involved in unpleasantness and possibly also to attention to pain to some extent. Lesions of cingulate cortex have been shown to reduce emotional value and motivation to avoid painful stimuli [71, 81]. Activity in ACC has been noted in response to pain in imaging studies [19, 34, 63, 96], and increased activity has been noted in chronic pain [16, 81]. Brain imaging has also shown activity in ACC in response to witnessing others experience pain [96].
ACC receives input from medial and intralaminar thalamic nuclei with large receptive fields of nociceptive neurons [16, 69, 71, 81], and projects to the amygdala, mediodorsal thalamic nuclei, PAG, motor nuclei of the brainstem, and insula, indicating involvement in motivational-affective aspects and conditioned fear reaction to pain [81]. ACC can modulate affective aspects of sensory perception via pain expectation and is also involved in mediating attention and anticipation of noxious stimuli. Hypnotic suggestion has been reported to selectively alter the unpleasantness of pain along with reduced pain-evoked activity in ACC [81]. Distracting subjects during noxious stimulation has also been noted to alter ACC activation [34, 69]
Insular cortex
The insular cortex, commonly referred to as just insula, is proposed to mediate interoceptive information, i.e., information on the physiological condition of the body across a variety of domains as they relate to motivation, including sensations of pain and temperature [30, 34, 71], and how different threats affect homeostasis[30]. Brain-imaging studies have shown activity in insular cortex in response to experiencing pain [34, 63, 96], as well as witnessing others experiencing pain [96]. Lesions to insula have shown apparent reduction in pain affect and appropriate reactions to painful and threatening visual or auditory stimuli, but not pain threshold [71].
Anterior insula receives afferents from the posterior portion of the ventral medial nucleus of thalamus, which contains almost exclusively thermoreceptive and nociceptive neurons [16, 71, 81], as well as from mediodorsal and intralaminar nuclei of thalamus and from SII [16, 81]. The insula in turn has widespread connections to thalamic and cortical regions, suggesting an integrative role subserving appropriate, particularly autonomic, responses to stimuli [71, 81]. Connections from SII to insula and further on to amygdala and hippocampus suggest a role in pain related learning and memory. The insula may integrate pain-related input from SII and thalamus with contextual information from other modalities before relaying to limbic structures [71].
Limbic system
The limbic system mediates aversive drive and thus influences motivational components and determines purposeful behavior [52]. The amygdala receives both noxious and innocuous signals by way of the parabrachial nuclei, and is an important hub for processing the threatening aspect of pain. Projections from amygdala are widespread to several brain areas, such as hypothalamus, brainstem monoamine cell bodies, nucleus tractus solitarious and PAG [72]. The connections to these brain regions are thought to contribute to activation of species specific defense responses, i.e., hormonal, cardiovascular and behavioral reactions [72]. Both direct and indirect spino-limbic projections indicate that parallel channels ensure that critical information reaches hypothalamus in order to regulate homeostasis [81]. Research suggests inhibition of amygdala may help reduce experience of, and emotional responses to, chronic pain [72], whereas stimulation of limbic structures can induce behavior which is otherwise associated with pain [43].
Brain stem
Autonomic reflexes and voluntary actions are generated after the rostral transmission reaches the brainstem and cerebrum [87]. This is also a major site for activation of descending modulation of pain. SMT projects to several midbrain nuclei, perhaps most prominently PAG [16, 52, 65, 67, 87, 90, 95] and nucleus cuneiformis [65, 87, 90] in the midbrain reticular formation.
PAG is a major locus for integration of homeostatic control [52] and is noted for its importance in descending modulation of pain [31, 52, 95]. PAG receives input from cerebral cortex [7, 95], limbic structures [69, 95], and spinal cord [95]. Electrical stimulation of PAG [12, 16, 31, 33, 43, 88, 90] and nucleus cuneiformis [97] inhibits response to wide spectrum of noxious stimuli, primarily via projections to NRM and adjacent nucleus magnocellularis in the medullary reticular formation [31, 69, 95, 97]. Stimulation of PAG also induces a behavioral state suggestive of fear [46, 90], suggesting that PAG likely is involved in complex behavioral responses to stressful or life-threatening situations [90].
The SRT terminates on several nuclei of medullary and pontine reticular formation [52, 87]. The reticular formation is believed to have several possible functions with regard to nociceptive transmission [87]. Several articles included in this review report that the reticular formation plays a crucial role in arousal [17, 37, 41] and consciousness [78]. Additionally, it may function as simple relay station to thalamic centers and the connections to autonomic nuclei indicate involvement in autonomic responses such as pupil dilation, tachycardia, increased blood pressure, etc. [16, 36, 87]. Certain nuclei may generate action potentials that inhibit neurons in the spinal cord [16, 22, 67, 87]. Certain nuclei in the reticular formation may facilitate transmission of STT through caudally directed excitatory neurons, enlarging the receptive field of STT in dorsal horn [87].
Perhaps the most prominent reticular formation nuclei in pain modulation are in the rostroventral medulla (RVM), including nucleus gigantocellularis, nucleus paragigantocellularis, and NRM [10, 16, 83, 87, 90]. NRM has diffuse projections to the dorsal horn [69]. A large portion of the neurons in the raphe nuclei contain serotonin. The serotonergic projections from raphe nuclei to the spinal cord are the major source of serotonin in the spinal cord [90]. Stimulation of NRM leads to release of serotonin in the spinal cord [69].
Another major termination of SRT fibers, primarily those originating from lamina I, is the parabrachial region in the brainstem, which in turn is reported to project the amygdala [16, 72, 90]. Collaterals of SRT also terminate among almost all catecholamine cell groups of medulla and pons, including A5 and A7, and the locus ceruleus (A6) [90]. The parabrachial nuclei and the A5-A7 cell groups also receive input from PAG and in turn project to the spinal cord, indicating involvement in the descending modulation of pain [16, 90]. The A5-A7 cell groups are the primary sources of noradrenergic projections to the spinal cord [90].
Other supraspinal regions
There are several additional supraspinal brain regions involved in pain processing. Several sources mention pain related activity in prefrontal cortex [30, 34, 38, 43, 49, 63, 81], without much detail on the possible function or role of this region in pain processing. Studies have also shown that stimulation of motor cortex can suppress pain [67, 81], indicating a role in pain perception and modulation.
Modulation
The body has several mechanisms for modulating pain signals at different levels along the nervous system. Modulation can result in both inhibition and facilitation of transmission and processing of pain. Descending modulation is exerted by three main neurochemical systems: noradrenergic, serotonergic, and opioidergic [77]. Figure 8 shows some of the supraspinal regions most prominently involved in pain modulation and their associated neurochemicals and afferent and efferent projections. The many parallel connections with different signs (excitation versus inhibition) in Fig. 8 give suggest that certain aspects of pain modulation perhaps can be modelled by interconnected dynamical systems. Suppose that there exists a balance between excitation and inhibition under normal circumstances. A mathematical model could then explore how the dynamics of the system change if the balance is perturbed, and perhaps lead to insight into the mechanism of some pathological pain conditions [26].
Enkephalins are a type of endogenous opiates that act on opiate receptors within the nervous system [11, 24, 45]. Enkephalin-containing interneurons in the dorsal horn make axo-axonic synapses to primary afferent terminals [11]. When the enkephalins bind to receptors on the target neuron, they hyperpolarize the neuron and reduce the release of neurotransmitter, thereby inhibiting signal transmission [11]. It is thought that these inhibitory neurons modulate reactivity to incoming pain signals [22, 24, 31, 87, 88], supposedly by large-fiber input triggering these cells to depolarize afferent terminals on nociceptors, thereby decreasing their synaptic effectiveness [7, 22, 36, 54].
Peripherally opioid receptors are present on thin nociceptive fibers [57, 75]. Opioids are less effective once sensitization has been elicited, thus preemptive analgesia is often better at reducing pain [29]. Furthermore, section of a peripheral nerve can lead to degeneration of the nerve and loss of opioid receptors, thereby reducing the responsiveness to opioids [28]. There are several other factors that can impact opioid responsiveness, such as accumulation of opioid antagonists and changes in non-opioid peptides [28].
Neurons originating in medullary reticular formation have high density of opiate receptors and are activated by enkephalin release [87]. Major brain stem regions involved in pain modulation are the RVM, PAG and the noradrenergic cell groups A5, A6 (locus ceruleus), and A7. There also exist non-endorphin synapses in the pain suppression system. Serotonin plays major role in producing analgesia, thus certain antidepressants have been effective in treating some intractable pain conditions [33, 77]. Norepinephrine is another neurotransmitter that plays a role in pain modulation. Inhibition at dorsal horn is mediated by a number of neurotransmitters, including amino acids such as γ-Aminobutyric acid
(GABA) and glycine [23, 60, 90], where GABA acts both pre- and post-synaptically and glycine post-synaptically [90].
Stimulation produced analgesia can be induced in several supraspinal areas, most located in the brainstem [77] such as NRM and PAG [8, 21, 33, 75]. The analgesia is generally attributed to the action of PAG on spinal cord neurons, most prominently indirectly through connections to NRM [31, 33, 69, 81, 95], the noradrenergic cell groups [65, 81] and parabrachial nuclei [16, 65, 90], which in turn send impulses along efferent fibers to spinal cord where they terminate most densely in the same layers of dorsal horn as the afferent pain fibers do [31, 33, 81, 95]. Axons of these neurons release serotonin [16, 31, 54, 87, 95] and norepinephrine [16, 54], which act by activating inhibitory interneurons which in turn exert pre-synaptic inhibition on primary pain afferents.
As mentioned above, another supraspinal area capable of inducing analgesia through electrical stimulation is the primary motor cortex. Chronic stimulation of motor cortex has been reported to relieve neuropathic pain in a somatotopically-specific fashion, suggesting important role of motor cortex in descending pain modulation [67, 81].
Pain facilitation (pronociception) is mediated via the medulla oblongata, where the dorsal reticular nucleus exerts unique pronociceptive effect [77]. Stimulation induces hyperalgesia in acute pain, and lesioning induces analgesia in both acute and sustained pain. The dorsal reticular nucleus projects to widespread areas of the brain, targeting areas of motivational-affective and pain-associated motor behaviors. Certain chronic pain conditions could be related to imbalance between pro- and anti-nociceptive processes [77].
Cognitive information can override endogenous pain modulation [24, 56]. Pain catastrophizing can have a number of impacts on pain such as dysregulation of the endogenous opioid pain-control system, activation of inflammatory processes, and several other physiologic responses, such as muscle tension, increased blood pressure and cardiovascular stress [20]. It has also been associated with increased activity in several cortical regions, mainly those associated with motivational-affective aspects of pain [20]. Similarly, hypnotic suggestions of pain can induce similar sensations of pain and brain response as if physical stimulation had been applied [49], and witnessing others in pain can create or intensify a pain experience [96]. Meanwhile, hypnotic suggestions for decreased unpleasantness of pain have shown altered activity in ACC, whilst suggestions for decreased pain intensity show decreased activity in SI and SII [49]. Cognitive behavioral interventions are common as pain treatments [34]. Improvements following this have been seen to be accompanied by reduced activation in brain regions involved in affective and cognitive modulation of pain, increased activity in regions involved in sensory processing, and better pain prediction [34].