Human surrogate models of neuropathic pain : PAIN (original) (raw)
1. Introduction
Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (Merskey and Bogduk, 1994). Current efforts to refine this definition focus on the terms ‘dysfunction’ and ‘nervous system’ with the intention to clarify that there has to be an identifiable lesion or disease process affecting the somatosensory system. Experimental models of neuropathic pain according to either one of these definitions are expected to imitate mechanisms of nerve damage within the peripheral or central parts of the somatosensory system and the ensuing processes of degeneration and regeneration. Whereas this approach to model the etiology and pathophysiology of the underlying disease process is the focus of various animal models of neuropathic pain, for obvious ethical reasons these processes cannot be induced in healthy human subjects.
Human surrogate models of neuropathic pain focus on the sensory signs and symptoms. On one hand, this is a limitation. On the other hand, the investigation of sensory symptoms exploits the unique human capacity for verbal communication, which allows the direct assessment of quality and intensity as well as location and duration of ongoing signs (pain, paraesthesia) and evoked signs (evoked pain, sensory loss) without relying on reflexes. In addition, laboratory studies in human surrogate models with electrophysiological and imaging techniques are immediately transferable to patient populations (e.g. García-Larrea et al., 2002). The following paragraphs outline the properties of existing human surrogate models of neuropathic pain, provide a framework for future models and their relationship to both animal models and clinical studies.
2. Three phases of pain mechanisms
Pain mechanisms can be divided into three phases (Cervero and Laird, 1991; Woolf and Salter, 2000):
- Phase 1 represents the transient activation of the nociceptive system by its adequate stimuli and processing of this information in the central nervous system.
- Phase 2 mechanisms represent the acute plasticity of the nociceptive system that is invoked with each injury and comprises reversible modulation of the nociceptive system.
- Phase 3 mechanisms represent chronic abnormal pain sensations due to modification of the nociceptive system.
These three sets of mechanisms are activated in different sequence in nociceptive vs. neuropathic pain (Table 1). The initiating event in nociceptive pain is actual or impending tissue damage, which leads to the activation of peripheral nociceptive nerve terminals by their adequate stimulus. This signal is conducted towards the central nervous system, where it is being processed according to the current balance of excitatory and inhibitory influences (Phase 1). Whenever actual tissue damage has occurred, Phase 2 mechanisms are also activated (peripheral and central sensitization, modulation of descending inhibition and facilitation). These mechanisms are part of the normal response of the nociceptive system (e.g. in postoperative pain) and they are usually reversible within hours or a few days. Modification of the nociceptive system (Phase 3; e.g. altered gene expression in primary nociceptive neurons, COX-2 upregulation in the spinal cord) may occur in chronic inflammatory diseases leading to long lasting changes in its responsiveness. These mechanisms contribute to chronic pain.
Comparison of nociceptive and neuropathic pain
The initiating event in neuropathic pain is damage to the nervous system, which leads to a loss of function (negative sensory signs). If this loss of function is accompanied by ongoing pain, there must be activation somewhere along the nociceptive system (e.g. peripheral neuroma, dorsal root ganglion, dorsal horn neurons or thalamic neurons). The generation of this ectopic activity is a consequence of modification of the nociceptive system (e.g. altered expression of sodium channels). Thus, neuropathic pain starts immediately with Phase 3 mechanisms. Once neural discharges are generated at one level of the nociceptive system, normal synaptic transmission (Phase 1) and normal modulation of the nociceptive system (Phase 2) occur at all higher levels of the system. Thus, nociceptive and neuropathic pains share most of the Phase 1 and 2 mechanisms, with the exception of the normal transduction process at the peripheral nerve terminals.
3. Clinical manifestations of pain mechanisms: neuropathic pain signs and symptoms
Although pain mechanisms themselves are usually not obvious in a given patient, they can be grouped according to observable clinical manifestations that they are likely to generate. Clinical manifestations basically consist of ongoing pain, evoked pain and sensory loss (Table 2).
Observable clinical manifestations of neuropathic pain and their putative underlying mechanisms
Ongoing pain and paraesthesia give evidence for spontaneous activity generated within the nociceptive system in the absence of the peripheral adequate stimulus. In the peripheral nervous system, ectopic impulses may be generated at a neuroma site or the dorsal root ganglion. A variety of changes in ion channel expression (subtypes of sodium, potassium and calcium channels) may be responsible for ectopic impulse generation. Since central neurons are spontaneously active under normal conditions, a reduction in inhibitory input is already sufficient to generate enhanced spontaneous activity in the central nervous system.
The positive sensory signs of mechanical hyperalgesia and allodynia can be due to either central sensitization (e.g. of spinal cord neurons), reduced descending inhibition or enhanced descending facilitation. The effects of central sensitization are regionally limited to the immediate vicinity of the affected peripheral nerve or segment, although they can cross the boundary of the innervation territory of a peripheral nerve (Sang et al., 1996). In contrast, the descending inhibition typically has remote effects (Millan, 2002); hence, a deficit in descending inhibition may be expected to influence the whole body. Peripheral and central sensitization may be distinguished according to the modality that is affected: peripheral sensitization leads to heat hyperalgesia, central sensitization to mechanical hyperalgesia (Treede et al., 1992). There is some evidence that paradoxical heat sensations and cold hyperalgesia may be due to the loss of central inhibition from a thermoreceptive pathway (Craig and Bushnell, 1994).
Sensory loss plays a prominent role in the assessment of neuropathic pain, because it gives evidence for the presence of damage to the somatosensory system. The pattern of affected modalities allows to distinguish which afferent fiber classes (Aβ, Aδ, C) and central pathways (dorsal column, spinothalamic tract) are involved in the nervous system damage. The spatial pattern of sensory loss allows conclusions about the site of damage.
4. Strengths and limitations of human surrogate models
Table 3 lists the signs and symptoms of neuropathic pain that are present in some commonly used human surrogate models. Note that most models elicit more than one symptom and that most symptoms are present in several models. For some of the symptoms, however, a sufficient model so far does not exist. Each model covers a specific set of symptoms determined by the underlying mechanisms they stand for. Thus, as before, we discuss the human surrogate models according to the observable clinical phenomena.
Pattern of representation of clinical characteristics of neuropathic pain in human surrogate models
4.1. Human surrogate models of ongoing pain and paraesthesia
Neuropathic pain is characterized by several sensory qualities (Bouhassira et al., 2004). Some neuropathic pains are reported as continuous and burning, others as paroxysmal and shooting. Although only little is known on how these different pain qualities are encoded in the nociceptive system, qualitatively similar sensations can be elicited experimentally in healthy human subjects.
A burning pain quality is a feature of experimental first and second degree burn injuries (Raja et al., 1984). Similar pain qualities are induced by topical application of capsaicin or mustard oil to the skin (Koltzenburg et al., 1994; Petersen and Rowbotham, 1999). Whereas the tonic burning pain quality might serve as a model for certain aspects of ongoing constant neuropathic pain, activation of the nociceptive system in these models occurs via adequate stimulation of its peripheral nerve terminals. Strictly speaking, these models therefore simulate nociceptive pain. There is a concern that these models may mimic inflammatory pain conditions better than neuropathic pain.
The unnatural dysaesthetic sensations that may be representative of certain paroxysmal neuropathic pain qualities are often described as being analogous to electrical stimulation (shooting, electric). Hence, electrical stimulation of nerve trunks might serve as a surrogate model of this type of neuropathic pain. There have been many clinical trials on analgesic efficacy with electrical stimulation, but those trials were not designed to model neuropathic pain (Scharein and Bromm, 1998). According to the different electrical excitability of large and small nerve fibers, electrical stimuli to the nerve trunk primarily activate large myelinated A-fibers. Since there is evidence that some neuropathic pains are mediated by large A-fibers (Campbell et al., 1988), electrical nerve stimulation may be a good model for these clinical entities.
Several strategies have been developed to favor C-fiber recruitment by electrical stimuli: intracutaneous electrodes (Koppert et al., 2001), punctate epicutaneous electrodes (Klein et al., 2004), and slow sine waves (Wallace et al., 1996).
Another ongoing symptom of neuropathic pain are paraesthesiae, which can be induced by reperfusion following nerve compression/ischemia. These sensations are accompanied by ectopic spontaneous activity in large myelinated A-fibers (Ochoa and Torebjörk, 1980), and are sometimes described as being painful (Reinert et al., 2000).
In summary, each quality of neuropathic pain is mimicked by at least one human surrogate model, but the clinical relevance of ongoing pain in those models has not been verified. This gap may be closed by asking neuropathic pain patients to compare the qualities of their clinical pain and the experimentally induced pain of these human surrogate models.
4.2. Human surrogate models of evoked pain
Dynamic mechanical allodynia has been described as a puzzling clinical phenomenon in many early studies on neuropathic pain (Lindblom and Verrillo, 1979), wherein gentle tactile stimuli elicit a pain sensation. Later it was recognized that this sensation is tested best with tactile stimuli applied in a stroking movement across the skin (Koltzenburg et al., 1992; Ochoa and Yarnitsky, 1993). Allodynia is also part of the sensory characteristics in the area of secondary hyperalgesia surrounding an injury site and of referred hyperalgesia in an area of referred visceral or muscle pain (Treede et al., 1992). Allodynia can be induced by injuries and without injury by intradermal capsaicin injection or electrical skin stimulation (Klein et al., 2004; LaMotte et al., 1991).
Punctate mechanical hyperalgesia occurs in similar conditions as dynamic mechanical allodynia, but in contrast to allodynia it is assessed with static contact by small probes such as v. Frey probes (Koltzenburg et al., 1992; LaMotte et al., 1991; Ziegler et al., 1999). Whereas dynamic mechanical allodynia appears to be maintained by a tonic sensitizing input from the periphery, static mechanical hyperalgesia is independent of a maintaining sensitizing input, and hence may reflect a more chronic mechanism than allodynia (Koltzenburg et al., 1994; LaMotte et al., 1991). Many pharmacological studies have used mechanical allodynia and punctate mechanical hyperalgesia as human surrogate models of neuropathic pain signs (Liu et al., 1998).
Hyperalgesia to cooling stimuli has also been listed as a cardinal symptom of neuropathic pain (Frost et al., 1988) and has not been reproduced successfully in any of the models of secondary hyperalgesia. Recently, a cold hyperalgesia was induced by topical application of high concentrations of menthol (Wasner et al., 2004). This model may be useful in the future to study both mechanisms and treatment of cold hyperalgesia in neuropathic pain.
Paradoxical heat sensation is a phenomenon, where gentle cooling is perceived as hot or burning. It has been suggested to be a sign of central disinhibition of a polymodal nociceptive pathway which is supposed to be under tonic inhibitory control by a thermoreceptive pathway (Craig and Bushnell, 1994). It is easily induced in healthy subjects by preferential A-fiber block by nerve compression (Fruhstorfer, 1984).
In summary, a variety of models have been published that allow the study of treatment options for mechanical allodynia, pinprick hyperalgesia, cold hyperalgesia and heat hyperalgesia. Validated human surrogate models for radiation and after sensations have yet to be developed.
4.3. Human surrogate models of sensory loss
A selective sensory loss of functions mediated by Aβ- and Aδ-fibers can be induced by a transient ischemic nerve block. For this purpose, either the whole limb is rendered ischemic by inflating a blood pressure cuff above systolic blood pressure, or pressure is exerted directly onto a nerve overlying a bone (superficial radial at the wrist, ulnar at the elbow, peroneal below the knee). The transient sensory loss includes tactile and cold detection, and with a longer latency also the detection of punctate mechanical stimuli (Fruhstorfer, 1984; Ziegler et al., 1999). This pattern of partial sensory loss is similar to that in certain patients with neuropathic pain (Baumgärtner et al., 2002).
A selective sensory loss of functions mediated by primary nociceptive afferents expressing the TRPV1 receptor (capsaicin-sensitive afferents) can be induced by long-term epicutaneous application of capsaicin (Magerl et al., 2001; Nolano et al., 1999). Skin biopsies have shown that the TRPV1 expressing nerve fibers withdraw from epidermis and dermis, and regrow after cessation of the treatment. This selective nerve block affects mostly C-fibers. The sensory loss includes heat pain perception with only minor effects on mechanical pain perception. This is a model of partial nociceptive denervation lasting for days to a few weeks. It is presently not clear, which aspects of neuropathic pain might be mimicked by this model.
Total nerve block with local anaesthetic mimics regional deafferentiation. Several studies have investigated the effects of this model on cortical reorganization and sensory capacities, reproducing certain aspects of phantom limb sensations and phantom limb pain (e.g. Gandevia and Phegan, 1999).
In summary, patterns of partial or complete sensory loss similar to those in neuropathic pain patients can be induced transiently in healthy subjects, but the clinical relevance of those human surrogate models has yet to be evaluated.
5. Conclusions
Human surrogate models of neuropathic pain focus on the mechanisms of symptom generation. As listed in this text, a vast array of human surrogate models exists for ongoing signs, for positive sensory signs and for sensory loss. The gaps in our knowledge about the relationship between neurobiological mechanisms and the resulting pattern of sensory signs and symptoms can be closed by studies that evaluate a standardized set of variables (e.g. quantitative sensory tests, pain questionnaires) in a variety of human surrogate models with known mechanisms.
By design, human surrogate models of neuropathic pain involve a reversible modulation of the properties of the nociceptive system, i.e. its acute plasticity (Phase 2). They usually do not create a long-lasting and potentially irreversible modification (Phase 3). The denervation and ectopic activity of Phase 3 can be modeled to a certain extent by transient nerve compression-ischemia and by topical capsaicin. By being models for Phase 2 mechanisms, however, most human surrogate models mimic sensory symptoms that may occur in both neuropathic and nociceptive pain (e.g. central sensitization). This means that findings from such human surrogate models are relevant for, but not specific to neuropathic pain.
Each sensory finding is compatible with several neurobiological and neuropharmacological mechanisms, because of convergence in the generation of clinical manifestations. By using the level of clinical manifestations (signs and symptoms) for the classification of neuropathic pain and its models (human and animal), an intermediate level of sophistication can be created in between highly sophisticated pharmacological mechanisms of action and a simple clinical overall assessment of daily pain intensity. We propose that this intermediate level of sophistication is useful and necessary for advances in translational research. A more thorough characterization of human surrogate models may in the future lead to a refinement of the proposed grouping scheme, e.g. if the differential clinical manifestations of descending facilitation and spinal sensitization can be identified. Already at the present stage, human surrogate models of neuropathic pain are useful for the investigation of pharmacological mechanisms of action and therapeutic efficacy, because they are based on identical assessment techniques as in the actual patient studies.
Acknowledgements
The authors' work has been supported by the Deutsche Forschungsgemeinschaft (Tr 236/16-1) and the Bundesministerium für Bildung und Forschung (01EM0107).
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Keywords:
Hyperalgesia; Allodynia; Sensory loss; Translational research; Animal models; Quantitative sensory testing; Pain questionnaires
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