Primary afferent neurons have peripheral terminals that detect external stimuli, cell bodies located in the dorsal root ganglia for perception from the body, and central terminals in the spinal cord. Aside from the unusual exception of trigeminal proprioceptive neurons, which have their cell bodies in the central nervous system, primary afferent neurons have their cell bodies in the peripheral nervous system: first-order neurons conveying perception from the face have cell bodies in the trigeminal ganglia and project to the brainstem, and first-order neurons carrying information from the body have cell bodies in the dorsal root ganglia and project to the spinal cord.
Nociceptors are high-threshold stimulus detectors and include the thinly myelinated A-δ fibers and unmyelinated C-fibers.7 Nociceptors represent one of several functional groups of sensory fibers in peripheral nerves (Table 89-2), including those fibers involved in mediating proprioception, low-threshold mechanoreception, vibration sense, and innocuous thermal stimuli (Table 89-3). For both A-δ fibers and C-fibers, the distal dendritic inputs are simply bare nerve endings, as opposed to, for example, the more elaborate pacinian corpuscles and muscle spindles used to detect vibration and proprioception. The A-δ fibers mediate acute, precisely localized initial pain. A-δ fibers fall into 2 groups based on electrophysiological studies of the stimuli required for their activation: Type 1 or high-threshold mechanical A-δ nociceptors have high heat thresholds (>50°C) and respond to mechanical stimuli as well. Type 2 or low-threshold mechanical A-δ fibers have a much lower heat threshold but a very high mechanical threshold. Type 1 A-δ fibers most likely mediate pain due to pinprick, and Type 2 A-δ fibers convey the initial response to noxious heat.
Table 89-2 Classification of Fibers Found in Peripheral Nerves ||Download (.pdf)
Table 89-2 Classification of Fibers Found in Peripheral Nerves
|Fiber Type||Innervation||Mean Diameter (μm)||Mean Conduction Velocity (m/s)|
|A-β||Cutaneous touch and pressure afferent fibers||8||50|
|A-δ||Mechanoreceptors, nociceptors, thermoreceptors||2-3||15|
|C||Mechanoreceptors, nociceptors, thermoreceptors, sympathetic preganglionic||1||1|
|A-α||Primary muscle spindle, motor to skeletal muscle||15||100|
|A-γ||Motor to muscle spindle||6||20|
Table 89-3 Functional Classification of Primary Afferent Nociceptors ||Download (.pdf)
Table 89-3 Functional Classification of Primary Afferent Nociceptors
|Type of Fiber||Nociceptor Type||Noxious Stimuli Detected|
|A-δ (2-30 m/s)||AM||Mechanical|
|AMC||Mechanical and cold|
|AMH type I||Mechanical, heat >53°C|
|AMH type II||Mechanical, heat <51°C|
|C-fiber (0.5-2 m/s)||CM||Mechanical|
|C-Chem||Chemical (algesic and pruritic)|
|CMib||None in resting state, mechanical (after activation)|
C-fibers convey poorly localized, delayed pain. Most C-fibers are also polymodal, although a subset of mechanically insensitive, heat-responsive neurons develops mechanical sensitivity following tissue injury. These neurons are known as "silent nociceptors" and are thought to be particularly important in the development of facilitated pain states.8 Interestingly, distinct sets of C-fibers appear to be involved in itch9 as well as pleasant touch.10
C-fibers can be divided into nonpeptidergic and peptidergic neurons. The nonpeptidergic population uses only the traditional excitatory neurotransmitter glutamate and expresses the c-Ret neurotrophin receptor, which binds the ligand glial-derived neurotrophic factor (GDNF).11 Peptidergic C-fibers use both glutamate and neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP), as neurotransmitters. They express the TrkA neurotrophin receptor, which binds the ligand nerve growth factor (NGF).
Knowledge about peripheral fibers involved in nociception allows us to formulate key concepts that relate not only to the encoding and transmission in the periphery but to the entire afferent system. First, there is a high degree of segregation of afferent information. This is reflected in the labeled lines hypothesis,12 in which different receptors on different types of neurons encode information specific to different stimuli, such as cold, hot, or high-threshold mechanosensation. We see that this spatial segregation of the structures responsible for particular types or components of the painful experience is preserved in the spinal cord, thalamus, and higher brain regions as well.
Second, and in contrast, many nociceptors and other higher-order neurons are polymodal; the convergence and integration of particular types of inputs determine the properties of a response. Thunberg's thermal grill illusion in 1896 demonstrates an interesting example of the complexity of convergence: the combination of innocuous cool and warm stimuli applied in a grid produces a noxious sensation of heat,13 despite the fact that neither component was noxious. The proposed explanation is that first-order neurons sensitive to innocuous cool converge on the same higher-order neurons as those activated by noxious cold; however, there is basal inhibition of the innocuous signal. The simultaneous warm stimulus in the grid removes that inhibition, allowing innocuous cool stimuli to cause pain.
The central axons of nociceptors enter the gray matter of the spinal cord via the dorsal roots and synapse on second-order neurons in the dorsal horn of the spinal cord (Fig. 89-4). Some primary afferent fibers traverse caudally or rostrally 1 to 2 segments in the tract of Lissauer prior to synapsing. The gray matter of the spinal cord is organized into 10 laminae (of Rexed). Laminae I to V compose the dorsal horn of the spinal cord (Fig. 89-5). Terminals of different afferent fiber types are separated spatially in the spinal cord. C-fibers terminate superficially within laminae I and II of the dorsal horn (lamina II is termed the substantia gelatinosa, based on its appearance); however, the segregation of fiber type is even more detailed. Most peptidergic C-fibers project to lamina I and the dorsal or outer part of lamina II, and nonpeptidergic C-fibers tend to project more ventrally to the midregion of lamina II. A-δ fibers project to lamina I as well as to lamina V. The large myelinated A-β fibers that mediate light touch project to the deeper laminae (III, IV, and V) as well as to a group of neurons in the ventral-most area of lamina II that express the γ isoform of protein kinase C (PKC-γ).
Cross-section of the spinal cord. Schematic of the spinal cord displays basic anatomic features. Cell bodies of second-order sensory neurons are located predominantly in the dorsal horn. Cell bodies of motor neurons are localized to the ventral horn. Nociceptive primary afferents may ascend or descend, covering as many as 6 spinal levels in the Lissauer tract prior to synapsing on second-order projection neurons and interneurons. Ascending and descending tracts in the white matter are not shown.
There is a very precise laminar organization of the dorsal horn of the spinal cord; subsets of primary afferent fibers target spinal neurons within discrete laminae. The unmyelinated, peptidergic C (red), and myelinated A-δ nociceptors (purple) terminate most superficially, synapsing upon large projection neurons (red) located in lamina I and interneurons (green) located in outer lamina II. The unmyelinated, nonpeptidergic nociceptors (blue) target interneurons (blue) in the inner part of lamina II. By contrast, innocuous input carried by myelinated A-β fibers (orange) terminates on PKC-γ expressing interneurons in the ventral half of the inner lamina II. A second set of projection neurons within lamina V (purple) receive convergent input from A-δ and A-β fibers.
Thus neurons in lamina I generally respond to noxious stimulation and neurons in layers III and IV respond to innocuous stimuli. Layer V neurons receive dual noxious and non-noxious stimuli and are therefore known as wide dynamic range (WDR) neurons.
Recall that large A-α and A-β sensory fibers that mediate vibration, proprioception, and touch ascend ipsilaterally in the dorsal columns after sending branches that synapse within the deep laminae of the spinal cord. Indeed, some evidence suggests a role for the dorsal columns as well in pain signaling. Inputs from the large fibers may reduce the ascending transmission of nociceptive inputs.14 Indeed, the dorsal columns themselves may transmit pain signals, as suggested by the reduction in visceral pain after dorsal column lesions.15
It is important to point out that most neurons in the dorsal horn of the spinal cord are interneurons, both inhibitory and excitatory, rather than the second-order projection neurons mentioned previously. Equally important is the recognition of the role of non-neuronal cells in the dorsal horn, such as microglia, in modulating neurotransmission. Thus the dorsal horn plays a primary role in sensory integration and modulation, as well as in transmission of nociceptive information. As will be covered, these functions are critical in modulating the gain of the nociceptive system and generating states of sensory sensitization.
The major projection neurons conveying the output from the dorsal horn reside in laminae I and V. These cells comprise the second-order neurons in the spinothalamic (anterolateral) tract, which carries sensory and discriminative information about painful stimuli to the thalamus. Projections to the posterolateral thalamus, near the terminals from the dorsal column/medial lemniscus pathway, transmit discriminative information about the nature of a noxious stimulus. In contrast, connections to the medial thalamic nuclei convey information associated with the affective component of pain. Separation of information from the superficial and deep layers of the spinal cord appears to be preserved in the thalamus.
Substantial nociceptive information passes from the dorsal horn to the brainstem via the spinobulbar tracts. This projection system terminates in 4 areas of the brainstem: the parabrachial region of the dorsolateral pons, the periaqueductal gray, regions of catecholamine cell groups, and the brainstem reticular formation. The parabrachial region of the pons provides a rapid connection to the amygdala, which mediates the aversive properties of pain; the periaqueductal gray balances ascending noxious inputs with descending pain-suppressing signals.
The integration and processing of nociceptive information (ie, pain) in the brain is perhaps the most difficult to study—largely due to its high degree of complexity. Indeed, much debate has transpired with regard to pain as a discriminative sense as opposed to an emotional experience.16 Pain has not only a sensory dimension but an affective one as well. The affective component of pain is comprised of the unpleasant emotional feelings generated by pain and the associated desires to end or reduce pain.17 Thus the intensity of perceived pain depends not only on the nature of a painful stimulus, but also on several other independent factors: emotional state—what emotions will a painful stimulus evoke in an individual person, and how will these additional emotions balance against the current emotional state; cognitive state—has the person learned to anticipate the pain itself or a reward associated with the pain; and level of arousal—how does the overall responsiveness of the person modulate a painful stimulus? In this sense, even the simplest pain, nociceptive pain, undergoes modulation by the brain. Perhaps the clearest demonstrations of modulation of pain are the suppression of pain by strong emotional stimuli. For example, intense emotions surrounding battle and athletics have been shown to suppress the response to pain. The soldier needs to focus on surviving and the athlete on performance.18 Indeed, soldiers injured in battle "entirely denied pain,"19 at least to some extent due to the positive experience associated with survival and perhaps also due to the positive expectation of returning home. Similar responses occur in animals, in which expectation of a reward completely suppressed response to pain, known as the nocifensive response, in dogs.20 Such mechanisms can also clearly serve an evolutionary purpose, in that an animal's response to pain or injury can be suppressed in the presence of a predator or other danger.
Much has been learned about the different components of pain, suggesting that different regions of the brain are responsible for different aspects of pain processing, and that there are complex interactions between these different centers.21 Moreover, pain is tightly linked to the reward pathways. Indeed, there is substantial overlap between regions of the brain activated by reward signals and those activated by pain signals.22
The ascending tracts terminate in both the lateral and medial thalamic nuclei. The lateral nuclei and their projections to primary sensory cortex transmit discriminatory pain, the perceptual identification of a precisely specified location, nature, and intensity of a noxious stimulus. The projections to the medial thalamus, in contrast, and the wide projections to limbic and frontal brain regions mediate the affective components of the pain experience.
One of the most expansive tools for studying pain has been functional imaging, including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). The assumption underlying these 2 techniques is that visualized blood flow and metabolic changes localized to precise regions reflect neuronal activity in the same locations. Although the metabolic effects of inhibitory neurons need to be considered in interpreting the imaging studies on a cellular level, brain imaging has consistently demonstrated regional effects of pain on the brain and has supported a structural segregation of discriminatory and affective pain processing.21 For example, heat pain in patients with somatoform pain disorder was associated with a hyperactive state of several limbic structures including the parahippocampal gyrus, amygdala, and anterior insula.23 Similar results were obtained in fibromyalgia patients during pain catastrophizing and inflammatory bowel patients during rectal distention. Additionally, the anterior insula and rostral anterior cingulate cortices were activated by both painful stimuli to volunteers and by observation of painful stimuli in their loved ones; in contrast, the posterior insula, sensorimotor cortex, and caudal anterior cingulated cortex were only activated by direct painful stimulation.24
Furthermore, these identified regions have been consistent with what might be expected, given prior neurologic knowledge from lesion-based studies. Thus pain asymbolia, the absence of the emotional or affective component of pain with preserved discriminative pain sensation, has been shown to occur after insular lesions.25
In conditioned place aversion tests, an animal associates a particular location with a noxious stimulus and subsequently learns to avoid that location. This anticipatory component of the affective pain response occurs in regions of the brain that are becoming more and more well defined. Indeed, animals with a lesion in the anterior cingulate do not undergo conditioned place aversion learning; that is, the rats do not avoid the place associated with a noxious stimulus.26 Furthermore, microinjection of an excitatory neurotransmitter into the anterior cingulate provided a substitute for the noxious stimulus and an antagonist blocked the development of the process.27 Thus excitatory stimulation of the anterior cingulate was sufficient to produce aversion to a particular location. Importantly, in all of these experiments, the nocifensive response was unaffected, suggesting that the affective dimension of pain—but not the sensory one—was selectively modulated.
The widespread changes in brain function associated with chronic pain conditions revealed by functional imaging studies support the presence of major effects of pain on cognition and mood, especially with changes in the frontal and limbic regions, respectively. In fact, degree of depression in patients with fibromyalgia has been correlated with amygdala and anterior insular activity. Although such studies do not "prove" that pain causes depression, they do highlight the connection and support a careful regard for a patient's mood in treating pain.
Chronic low back pain has been associated with reduced gray matter mass in the thalamus and the lateral prefrontal cortex.28 The effects of pain itself are difficult to separate from secondary effects due to drug use or lack of normal activity and use-dependent structural reinforcements or changes; nonetheless, similar imaging studies have documented decreased gray matter among patients with chronic headache, fibromyalgia, irritable bowel syndrome, and chronic regional pain syndrome. Although the regions identified in the different studies are not identical, they tend to involve regions used during learning and during painful stimulation applied to healthy subjects.
On the cellular level, animal data also support changes in the brain associated with chronic pain, in particular with neuropathic pain. Investigation of cortical neurons after nerve injury shows increased length and branching of layer II/III pyramidal neurons in the contralateral motor cortex.29
Another important but confounding consideration in studying pain is the placebo effect.30 Just as intense emotional experiences such as battle can suppress the sensation of painful stimuli, the anticipation of reward also can increase the pain threshold, suggesting that affective modulation of pain and the placebo response—pain relief due to the expectation of pain relief—operate via a common mechanism.31 The widespread influence of the placebo effect is indeed extraordinary; placebo analgesia has even been shown to correlate with changes in fMRI signals within the dorsal horn of the spinal cord.32 Similar brain regions are involved in the placebo effect and in opioid analgesia.33 Opioid antagonists can block the placebo effect,34 and opioid agonists can prevent increases in fMRI signal in response to a noxious stimulus.35 Thus the placebo mechanism may involve activation of the descending pain modulatory system, to which we will now turn our attention.
The power of descending modulation of the pain system was first recognized by Reynolds, who in 1969 found that electrical stimulation of the midbrain periaqueductal grey (PAG) produced analgesia sufficient for surgery in rats.36 Since then, the multiple descending projections from several brainstem centers have been investigated.
The best-characterized system originates in the periaqueductal grey and sends fibers to the rostral ventromedial medulla (RVM), which in turn projects via the dorsal part of the lateral funiculus to both superficial and deep laminae of the dorsal horn (see Fig. 89-1). The RVM is comprised of the serotonergic nucleus raphe magnus and adjacent reticular formation that are located in the midline near the pontomedullary junction. Within the RVM, cells are grouped as on-cells, off-cells, or neutral-cells, with regard to their firing pattern during a nocifensive withdrawal.37 Although the initial emphasis was on the inhibition of pain transmission, recent studies have led to a greater appreciation of both inhibition and enhancement of pain pathways by descending fibers. The inhibitory descending fibers primarily target and blunt the nociceptive inputs of C-fibers.38
The descending pathways of the PAG and RVM receive extensive inputs from higher brain centers, including the hypothalamus, amygdala, and prefrontal cortex. Inputs from the amygdala are associated with intense fear-behaviors, and opioid injection into the basolateral nucleus of the amygdala activates off-cells in the RVM, presumably reducing pain during times of extreme fear.39 In contrast, stimulation of the ventrolateral orbital cortex and anterior cingulate cortex mediates hyperalgesia by stimulating on-cells in the RVM.
In addition to the PAG-RVM pathways, the dorsal reticular nucleus and caudal ventrolateral medulla have also been demonstrated to mediate descending pain signal modulation that occurs at the level of the spinal cord.
Descending inputs can also be categorized by transmitter type. The major transmitters involved in the descending pain modulatory pathways are the endogenous opioids, noradrenalin, and serotonin (5-hydroxytryptamine, 5-HT). The 3 classes of endogenous opioids are enkephalins, β-endorphin, and dynorphins, and are found within neurons of different regions of the central nervous system. Enkephalins and dynorphins are found predominantly in the PAG, RVM, and dorsal horn of the spinal cord, and β-endorphin is found primarily in neurons within the hypothalamus. There are 3 major classes of opioid receptors, μ, δ, and κ, and a less well-understood orphan-type receptor. The role of the μ-opioid has been most securely established: knockout of the μ-opioid receptor abolishes the analgesic effect of morphine.40 The contributions of the other receptor types have not been as clearly documented. The δ-receptor agonists may produce analgesia, with fewer side effects than the μ-receptor agonists. The δ-receptor seems to be involved in the development of opioid tolerance, as well as in anxiety. The κ-receptor may be involved in stress-induced dysphoria. The G-protein–coupled opioid receptors exert inhibitory effects by 2 major mechanisms: they decrease calcium conductances and increase potassium conductance, which can act either presynaptically to decrease transmitter release or postsynaptically to inhibit signal propagation.
Noradrenergic bulbospinal fibers that originate in the locus ceruleus mediate antinociceptive properties41 and act through the G-protein–coupled adrenoceptors. α1-Adrenoceptors are coupled to Gq, leading to an activation of phospholipase C, increased intracellular calcium, and transmitter release; α2-adrenoceptors are coupled to Gi/o, which causes an increased potassium conductance and therefore membrane hyperpolarization and decreased transmitter release. The descending noradrenergic effects occur through the inhibitory α2-adrenoceptor effects on nociceptive terminals and through the activation of presynaptic α1-adrenoceptors on inhibitory interneurons.42,43 Thus noradrenergic inhibition of the nociceptive pathway occurs either through inhibition of the nociceptors or stimulation of the antinociceptive inhibitory interneurons.
Serotonergic descending fibers from the RVM can mediate both antinociceptive and pronociceptive effects, depending on the receptor types activated.42 Of the 14 subtypes of serotonin receptors, most of which are coupled to G-proteins, predominantly the 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT3 receptor subtypes are found in the spinal cord. Serotonin hyperpolarizes second-order neurons in the dorsal horn via Gi/o-coupled 5-HT1A receptors, which act by opening potassium channels and closing calcium channels. Unlike other serotonin receptors, the 5-HT3 receptor is ionotropic, and the binding of serotonin leads to the opening of a nonselective, cation-permeable channel also found in the superficial layers of the dorsal horn. It is located on the afferent fibers of nociceptors and functions to enhance transmitter release from these neurons.