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The term ‘pain’ has several diﬀerent connotations that are a potential source of confusion in its usage. The most frequent of such confusions consists in an equivocation of ﬁrst-and third-person aspects of the target phenomenon (Metzinger 2000). There is the consciously experienced subjective qualitative aspect of pain. In this sense, to feel pain indicates a state of suﬀering. This aspect is only experienced from the ﬁrst-person perspective and, arguably, is not directly accessible for empirical research operating from an objective, third-person perspective. Third-person aspects of pain are constituted by its neural underpinnings (e.g., the minimally suﬃcient neural correlate of the subjectively experienced, conscious quality of pain) and the functional properties, that is, the causal role, played by them in generating overt behavior, internal reactions, the formation of memories, etc. In this sense, pain is the percept that results from the activation of a speciﬁc sensory system, the nociceptive system, which is activated by external stimuli that threaten the integrity of the body, and by internal states of tissues such as an inﬂammatory process. As such, pain is a sensory experience similar to the experience of hearing a sound or tasting food as a consequence of the activation of the auditory, gustatory, or olfactory system. A comprehensive theory of pain will have to do justice to both aspects, the third-person and ﬁrst-person aspects, of pain.
Since the 1970s the following deﬁnition by the International Association for the Study of Pain has gained widespread acceptance (Merskey et al. 1979):
- Pain is an unpleasant sensory and emotional experience
- associated with actual or potential tissue damage
- or described in terms of such damage.
This deﬁnition emphasizes that pain has several components, including at least a sensory one and an aﬀective one. In most instances, pain is not a generalized feeling (Allgemeingefuhl ) such as hunger and thirst, but a localized sensation. The capacity to locate pain is due to the encoding of spatial information in the nociceptive system. Likewise, ﬂuctuations in the perceived intensity of pain can be related to intensity coding in the nociceptive system. The discriminative power and the precision of stimulus encoding in the nociceptive system have traditionally been under- estimated. In addition to this sensory-discriminative component, pain almost inevitably encompasses an aﬀective component, mostly of a negative hedonic quality, which is not a simple function of sensory intensity or quality. While pain may be a particularly unpleasant sensory experience, aﬀective components are present in other sensory systems as well: a person may like or dislike a certain type of music, and a meal may have a pleasant or unpleasant taste. These aﬀective or emotional components of sensory experience provide powerful drives to direct behavior (e.g., withdrawal, guarding, or avoidance behavior). The unpleasant emotional aspects of pain perception are therefore called the aﬀective-motivational component of pain. The aim of this research paper is to present the neural basis of both components of pain from the point of view of sensory physiology. In the last section, an outlook will be given as to how sensory physiology may provide hints to understanding the subjective experience of feeling pain.
1. The Nociceptive System
Many tissues such as the skin, mucous membranes, muscles, joints, bones, and parts of the viscera (with the notable exception of the brain itself ) are innervated by free endings of thin primary aﬀerent nerve ﬁbers (Raja et al. 1999). The adequate stimulus to activate these nerve endings is a strong mechanical or thermal stimulus, or one of a variety of chemicals that are either applied from the outside (as with a nettle sting or the application of hot peppers to mucous membranes) or generated within the tissue (such as bradykinin, serotonin, histamine, prostaglandins, etc.). Because they respond to several stimulus modalities, these nerve endings are said to be polymodal. The common denominator of these stimuli is that they indicate either actual or impending tissue damage. Sherrington summarized this concept in the term ‘noxious stimulus,’ and the sensory system that processes information on noxious stimuli is called the nociceptive system. More recently it was found that polymodality does not depend on actual tissue damage but may also be a property of the ion channels present in free nerve endings. Many nociceptive nerve endings express the so-called vanilloid receptor channel VR1 (Caterina and Julius 1999), which can be activated by a physical stimulus (heat), and by both exogenous (capsaicin and other hot spices) and endogenous chemicals (anandamide and other derivatives of membrane lipids).
Some primary nociceptive aﬀerents (A-ﬁbers) conduct nerve impulses relatively rapidly (about 20ms−1). because of the saltatory impulse conduction that is enabled by the presence of a myelin sheath; most of the primary nociceptive aﬀerents are unmyelinated C- ﬁbers and conduct slowly (about 1 ms−1).A-ﬁbers are involved in rapid behavioral responses and in motor reﬂexes. C-ﬁbers are involved in slower signaling processes, including the perception of a delayed ‘second pain’ after a single brief stimulus such as a pinprick, changes in the sensitivity of the nociceptive system (see Sect. 4), control of local blood vessels, and trophic functions (Holzer 1992).
Primary nociceptive aﬀerents make synaptic contact with second-order neurons in the dorsal horn of the spinal cord. Some nociceptive speciﬁc neurons have no other input, whereas another class of neurons receives convergent input from touch receptors in the skin. These neurons encode a wide range of mechanical stimulus intensities and are therefore called widedynamic-range neurons (Willis 1985). Spinal nociceptive neurons are subject to modulation by descending pathways from the brain stem, which are mostly inhibitory and utilize endogenous opioids, noradrenaline, and serotonin as neurotransmitters. The net result of primary aﬀerent inputs, descending modulation, and local interactions in the spinal cord dorsal horn is then projected to spinal motor nuclei in the ventral horn, spinal autonomic nuclei in the lateral horn, to the brain stem and to the contralateral somatosensory thalamus.
Via the spinoreticular and spinomesecephalic tract projection to the brain stem, noxious stimuli may activate autonomic reﬂex centers of the cardiovascular and respiratory system, the descending inhibition of the spinal cord dorsal horn, and the ascending reticular activating system (ARAS) that projects to the cerebral cortex. These projections are the neural basis for many autonomic reﬂexes elicited by pain, for the fact that one pain may inhibit another pain, and for the strong arousal reaction to painful stimuli.
Via the spinothalamic tract, the nociceptive pathways reach two groups of nuclei in the thalamus (Craig and Dostrovsky 1998). The lateral group is situated in the ventrobasal complex and is identical to the relay station of the tactile system. These thalamic nuclei project to the primary and secondary somatosensory cortex (SI and SII), and to the insula. The medial group is mostly situated within the white matter of the thalamus (intralaminar nuclei). These thalamic nuclei project to the anterior cingulate gyrus, the basal ganglia, and also nonspeciﬁcally to wide parts of the cerebral cortex. Since its original suggestion in the late 1960s (Melzack and Casey 1968), the concept that the lateral system processes the sensory discriminative component, and the medial system the aﬀective-motivational component of pain, is still a valid concept (Treede et al. 1999).
2. Sensory Discriminative Functions
The sensory discriminative component of pain may be divided into at least three aspects: stimulus localization, intensity discrimination, and quality discrimination. The human capacity to perceive the location of tissue damage is used in everyday medical practice, when doctors ask the question ‘where does it hurt?’ Sometimes, tissue damage and perceived pain are in diﬀerent locations, as in the case of a myocardial infarction, which may cause pain in the left arm. This phenomenon (referred pain) is due to convergence of visceral and cutaneous aﬀerents in the spinal cord. The activity of the spinal neurons does not reveal the aﬀerent source, and higher centers are assumed to project the resulting sensation along the more common pathway from the skin. Because of the mislocalization of pain originating from damage to the viscera and the precise localization of tactile stimuli at the ﬁngertips, localization of noxious stimuli has traditionally been ascribed to simultaneous activation of the tactile system. Tactile acuity, however, rapidly drops outside the ‘foveal’ areas of the ﬁngertips and lips. On the back of the hand, sequential tactile stimuli must be about 1 cm apart to be perceived as being given to separate locations. When laser-radiant heat pulses (which do not activate tactile aﬀerents) are given to the back of the hand, the sequential spatial discrimination threshold is also about 1 cm (Schlereth et al. 2001).
These psychophysical ﬁndings demonstrate that the nociceptive system in humans provides suﬃcient spatial information to account for our capacity to know where it hurts. What is the neural basis for this capacity? Receptive ﬁelds of nociceptive neurons show somatotopic organization in the spinal cord dorsal horn (Woolf and Fitzgerald 1986), lateral thalamus (Albe-Fessard et al. 1985), and the primary somatosensory cortex (Kenshalo and Willis 1991). Receptive ﬁeld sizes in SI are smaller than in the spinal cord and thalamus, possibly due to lateral inhibition, and match the pain localization capacity. Thus, all existing evidence favors the view that SI is involved in stimulus localization for the nociceptive system as well as the tactile system. Indirect evidence for this concept is provided by studies in humans that use measures of brain perfusion as parameters of activation (by positron emission tomography: PET). These studies suggest that only tasks with a stimulus-localization component activate SI, whereas studies with ﬁxed stimulus location do not (Treede et al. 1999).
The capacity to encode diﬀerent intensities of noxious stimuli is one of the criteria for identifying nociceptive neurons (Willis 1985). Intensity coding has been demonstrated for nociceptive neurons in SI and to a certain extent in SII, but also in medial thalamic nuclei. Intensity coding is a poor criterion for identifying neurons involved in sensory discriminative aspects of pain, because the aﬀective-motivational component of pain also depends on stimulus intensity. In a study that demonstrated the diﬀerent relative unpleasantness of experimental painful stimuli, perceived intensity and unpleasantness were both nevertheless related to stimulus intensity (Rainville et al. 1992).
Pain may have diﬀerent qualities such as burning, stinging, or aching. Neither the number of subjectively discriminable qualities nor their neural basis are known with suﬃcient precision. The polymodality of primary nociceptive aﬀerents seems to contradict the capacity for quality discrimination, but the response proﬁles to diﬀerent noxious stimuli diﬀer between diﬀerent aﬀerents. Quality discrimination in the nociceptive system is therefore likely to be due to a population code, similar to the encoding of the taste qualities in the gustatory system.
Current evidence supports the traditional view that the lateral nociceptive system subserves the sensory discriminative component of pain. Diﬀerent aspects of this pain component (detection, localization, intensity discrimination, quality) may be processed in parallel by separate pathways. In contrast to traditional views, there is no evidence that the tactile system participates in any of these functions. Thus, nociception is established as a sensory modality within the somatosensory system.
3. Aﬀective Motivational Functions
The aﬀective-motivational component of pain sensation encompasses several aspects that are closely related: the negative hedonic quality and emotional reactions, an increase in the arousal level and stimulus related selective attention, and the drive to terminate the stimulus causing this sensation. Some of these functions can be considered second-order sensory processing, whereas the latter is a premotor function. The aﬀective-motivational component of pain is classically associated with the medial nociceptive system, which in turn is connected to the limbic system.
One part of the medial nociceptive system, the anterior cingulate cortex, has recently gained much publicity, because virtually all PET studies of acute pain gave evidence of activation in that area, including one study in which pain was elicited as an illusion by the interaction of two nonpainful stimuli (Craig et al. 1996). Electrophysiological recordings in humans also show activity in this area (Treede et al. 1999). The anterior cingulate cortex is a functionally heterogeneous brain area that has been implicated in the integration of aﬀect, cognition, and response selection in addition to aspects of social behavior (for review, see Devinsky et al. 1995). Passive functions (emotion, attention) are represented more frontally, whereas a premotor part of the anterior cingulate cortex is situated more posteriorly, below the supplementary motor area. It is still debated, whether the anterior cingulate cortex may contain a nociceptive-speciﬁc area, or whether painful stimuli nonspeciﬁcally recruit several parts of the large cingulate gyrus.
The aﬀective-motivational component of pain may also be processed in the insula. The contralateral insula was activated almost as frequently in human PET studies of acute pain as the anterior cingulate cortex (Casey and Minoshima 1997). Microstimulation in a thalamic nucleus that projects to the insula elicited pain with a strong aﬀective component only in those patients who had previously experienced such pain either due to panic attacks or due to angina pectoris (Lenz et al. 1995). These observations suggest that the insula may be part of a sensory limbic projection pathway for pain sensation. The insula projects to the amygdala (Augustine 1996), which is a part of the limbic system that is associated with emotions.
4. Plasticity Of The Nociceptive System
As in all other sensory systems, the repeated presentation of noxious stimuli or the exposure of the nociceptive system to stimuli of long duration may lead to a reduction in the intensity of the evoked response (habituation and adaptation). A unique property of the nociceptive system is that under many circumstances the prior presentation of the adequate stimulus may actually enhance subsequent responses (Treede et al. 1992). This enhancement is called sensitization and it may occur at both the peripheral terminals of primary nociceptive aﬀerents and within the central nervous system. Sensitization refers to a leftward shift in the function that relates the neural response to stimulus intensity. It is characterized by a drop in threshold and an increase in the response to suprathreshold stimuli. Spontaneous activity may also result from sensitization.
The perceptual correlate of sensitization is hyperalgesia, which is characterized by a drop in pain threshold and an enhanced painfulness of suprathreshold stimuli. Even minor tissue injury elicits a transient state of hyperalgesia, both of the injured tissue itself ( primary hyperalgesia) and in surrounding uninjured skin (secondary hyperalgesia). Primary hyperalgesia is characterized by a lowered pain threshold for both mechanical and heat stimuli. Secondary hyperalgesia is characterized by a lowered pain threshold for mechanical stimuli only.
In primary hyperalgesia, the heat pain threshold may drop below the normal body temperature, which then starts to act as an adequate stimulus for the nociceptive system, leading to ongoing pain. Such pain may, for example, occur in inﬂammatory conditions and is rationally treated by cooling. The neural basis of primary hyperalgesia to heat stimuli is peripheral sensitization of primary nociceptive aﬀerents by shifts in the temperature sensitivity of vanilloid receptors and related modiﬁcations of other ion channels (Cesare et al. 1999).
In secondary hyperalgesia, the mechanical pain threshold may drop in such a way that even gentle stimuli such as movement of cotton wool across the skin is perceived as painful (allodynia). Normal weight bearing on the sole of the feet or contact with clothing then start to act as an adequate stimulus for the nociceptive system, leading to functional deﬁcits by avoidance behavior. Such pain may also occur chronically following lesions of the nervous system (neuropathic pain), and this pain is particularly resistant to current treatment modalities. The neural basis of secondary hyperalgesia to mechanical stimuli is central sensitization of nociceptive neurons in the spinal cord by modiﬁcations of the synaptic transmission from Aß-ﬁber mechanoreceptors that normally signal touch and from A-ﬁber nociceptors (Ziegler et al. 1999).
Central sensitization of the nociceptive system involves the activation of NMDA (N-methyl-D-aspartate) glutamate receptors in the postsynaptic neuron and several additional mechanisms. The intracellular signal pathways are similar to those found for long-term potentiation (LTP) of synaptic eﬃcacy in the hippocampus, which is thought to be related to learning and memory. Both LTP and the opposing mechanism long-term depression (LTD) have been observed in slice preparations of the spinal cord using stimulation protocols similar to those that were found to be eﬀective in slice preparations from the hippocampus or neocortex. In the intact organism, the triggering of LTP in the spinal cord is antagonized by the endogenous descending inhibition (Sandkuhler 2000). The implications of these mechanisms for the causes of chronic pain are important but not yet fully understood. On the one hand, the intracellular signal pathways of LTP inﬂuence gene expression and may thus alter the function of nociceptive neurons for long periods of time. On the other hand, deﬁciencies in the balance between excitatory and inhibitory inﬂuences on the spinal cord may be a decisive factor in pain chroniﬁcation.
5. Epilogue: Pain And The Brain
If reading the preceding sections have left the impression that the neural basis of actually feeling pain has not been addressed, this impression is correct. It is evident that pain exists only as long as it is being felt by a person. Thus, trying to understand the pain experience as a whole leads into the general mind– body problem, which is a complex philosophical issue (for a more general account of how personal-level and subpersonal-level descriptions of pain can be combined, see Bieri 1995). This research paper has intentionally left out the intimate relationship of the subjective pain experience and consciousness. Instead, the preceding sections have described the neural pathways that signal tissue damage and how some of their known properties explain otherwise puzzling phenomena such as the allodynia of neuropathic pain states, where lightly touching the skin may evoke unbearable pain. But how the brain ultimately synthesizes the conscious perception of pain remains a mystery. A few simple examples, however, show that the brain does synthesize this perception:
(a) Blocking the neural pathways between the damaged tissue and the brain (e.g., by a local anesthetic in the dentist’s oﬃce) creates a situation where there is tissue damage but no pain.
(b) Activation of nociceptive pathways by electrical stimulation within the thalamus may elicit a vivid perception of the pain of a heart attack. In this situation there is pain but no tissue damage.
In other words, a foot cannot hurt by itself, but a brain can perceive a hurting foot. The latter is possible even in the absence of the foot, as observed in phantom limb pain. Pain due to proximal activation of the nociceptive system is called projected pain, because here the normal mechanisms of pain perception are particularly evident: pain sensation is synthesized in the brain, but is then projected into the peripheral receptive ﬁeld of the active brain areas. Pain due to peripheral activation of nociceptive aﬀerents is called nociceptive pain, but again the pain sensation is synthesized in the brain and projected into the peripheral receptive ﬁeld, which happens to be the site of tissue damage. This model of pain projection into receptive ﬁelds is simpliﬁed and does not include the central representation of the body image in brain areas such as the posterior parietal cortex, but this much should be apparent: pain is always in the brain.
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