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Clinical and pre-clinical pain assessment: Are we measuring the same thing?
Pain 135 (2008) 7–10 www.elsevier.com/locate/pain
Topical review
Clinical and pre-clinical pain assessment: Are we measuring the same thing? C.J. Vierck
a,*
, P.T. Hansson c, R.P. Yezierski
b
a
Department of Neuroscience, College of Medicine, Comprehensive Center for Pain Research, University of Florida, 200 Newell Drive, McKnight Brain Institute, Gainesville, FL, USA b Department of Orthodontics, College of Dentistry, Comprehensive Center for Pain Research, University of Florida, Gainesville, FL, USA c Department of Molecular Medicine and Surgery, Section of Clinical Pain Research, Karolinska Institutet and Department of Neurosurgery, Pain Center, Karolinska University Hospital, Stockholm, Sweden Received 4 December 2007; received in revised form 14 December 2007; accepted 18 December 2007
1. Introduction Assessment of clinical pain presents a unique problem compared to other major health conditions, such as heart disease or cancer, which can be detected by objective biological measurements. Diagnosis of chronic pain depends upon subjective reports by patients on the presence and intensity of pain. However, comparable reports on sensory attributes cannot be obtained from laboratory animals without language skills. Nevertheless, attempts to assess chronic pain in non-human species have involved observations of spontaneous behavioral or physiological reactions to presumed sources of pain. Unfortunately, spontaneous events such as vocalizations, autotomy/overgrooming, sleep disruption or autonomic activation do not qualify as direct measures of pain. When autotomy or overgrooming occurs, the eliciting stimulus is unknown – it could be numbness with analgesia or a non-painful paresthesia. Autotomy and grooming are not always associated with pain, and either can be assumed to exist in the absence of pain. Sleep disruption and autonomic dysregulation can be associated with and can exacerbate chronic pain [7], but neither results only from chronic pain. If sleep disruption were to be used as a primary measure of pain for development of analgesics, an effective compound might act directly on circuits regulating sleep cycles but have no effect on pain. Similarly, low dose systemic morphine directly attenuates *
Corresponding author. Tel./fax: +1 352 371 2378. E-mail address: [email protected]fl.edu (C.J. Vierck).
vocalizations of animals performing a food reinforcement task in the absence of any nociceptive stimulation [4]. Morphine reduces pain sensitivity, but this conclusion is not justified on the basis of an effect on vocalizations. Therefore, spontaneous behavioral or physiological events can complement but not replace direct measurements of pain or pain sensitivity. 2. Assessment of pain sensitivity of human and laboratory animal subjects In the present article, efforts are made to relate assessment of pain in human and laboratory animal subjects. The use of comparable methods in pre-clinical and clinical studies is critical to successful translational research. In this effort, assessment of pain sensitivity can be approached similarly with behavioral observations of humans and laboratory animals. Altered sensitivities of humans to somatosensory stimulation can validate ratings of ongoing pain, and for some conditions (e.g., fibromyalgia) diagnostic procedures include ratings of sensations generated by applied stimuli. Stimulus– response functions for escape from nociceptive stimulation can provide comparable information for laboratory animals. For both humans and laboratory animals, two principals are critical for evaluation of pain sensitivity. Measures of pain must: (1) reveal transmission over nociceptive pathways that extend to the cerebral cortex; and (2) require processing of sensory intensity in comparison with previous pain experiences. Importantly,
0304-3959/$32.00 Ó 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2007.12.008
8
C.J. Vierck et al. / Pain 135 (2008) 7–10
evaluation and reporting of pain intensity cannot occur without prior learning by either humans or laboratory animals. However, pain research with laboratory animals has relied historically upon observations of innate reflex responses that do not require cerebral processing of sensory intensity and are not dependent upon experience (learning). Reflex responses result from activation and modulation of spinal and supraspinal circuits that are distinct from pain transmission pathways from the periphery to cerebral sites mediating sensory, emotional, and motivational reactions to pain. Evidence from human imaging studies shows that cerebral cortical structures participate in the conscious perception of pain [6]. Also, functional labeling of the brain in response to nociceptive stimulation of laboratory animals supports the importance of cortical processing in pre-clinical models of pain [3]. Further demonstrating an essential contribution of high order processing are repeated validations of assessment instruments (e.g., McGill Pain Questionnaire) that emphasize cortically dependent psychosocial components of the pain experience. Therefore, it is imperative that assessments of pain in laboratory animals quantify behavioral responses to sensory experiences that are cortically mediated. Otherwise, behavioral assessment cannot provide a basis for delineation of fundamental mechanisms or identification of therapeutic targets or decisions regarding drug discovery and evaluation. If we are not getting the right answers with behavioral assessment there is no way we are going to succeed with translation from preclinical to clinical trials of therapeutic efficacy. 3. Evaluation of pain sensitivity in laboratory animals Consequent to appearance of the gate-control theory, there was excitement that nociceptive transmission could be controlled at synaptic relays in the spinal dorsal horn. Reflex tests have been used almost exclusively to reveal these effects on nociceptive transmission in waking animals. However, to show the relevance of reflex modulation to supraspinal pain processing, spinothalamic projection neurons must be affected identically to motoneurons in reflex circuits. Recordings from spinothalamic cells and motoneurons have rarely been compared directly and are necessarily obtained from preparations with unknown combinations of nociceptive inhibition and facilitation from anesthesia and surgical dissection. Furthermore, modern imaging studies have demonstrated that pain experiences are not dictated entirely by activity of spinothalamic neurons [5]. When direct comparisons have been made between reflex responses and cortically dependent operant escape tests, consistently different, sometimes opposite, effects have been demonstrated. For normal animals, stimulus– response functions for reflex and escape responses differ for heat, cold, and electrical stimulation, as do effects of
age, gender and the estrus cycle (e.g., [24,25]). A variety of experimental manipulations differentially affect reflex and escape responses; these include: morphine, naloxone, stress, morphine plus stress, naloxone plus stress, subcutaneous formalin injection, cutaneous application of mustard oil, chronic constrictive nerve injury, spinal white matter lesions (dorsolateral column, dorsal quadrant, anterolateral column, lateral hemisection), injury to spinal gray matter (quisqualic acid and selective neurotoxins SP-sap and SSP-sap), and i.p. or intrathecal injection of icilin (e.g., [11,19,20,22,23,26,27,29]). In these studies, operant effects have been consistent with expectations from human studies, but reflex effects have not. This is not to say that reflex testing has no utility in pain research. For example, the actions of opiates on spinal circuits were originally characterized with reflex tests. However, it is now apparent that complete reliance on reflex methods is not advisable, and reflex modulation cannot be equated with pain modulation. 4. Are reflex measures useful in translation of animal studies to humans? The use of reflex measures has been dictated by an interest in efficiency, but should speed of data collection be the primary consideration in selecting behavioral measures? Obtaining misleading results is the epitome of inefficiency. For example, pharmacologists would not attempt to understand mechanisms of action at receptor A with agonists or antagonists that bind to receptor B. This analogy applies to actions on reflexes (circuit B) which purport to reveal effects on pain (circuit A). Similarly, few would contend that visual sensations could be modeled by studying the pupillary light reflex or that conscious auditory experience can be revealed by studying startle or cephalogyric reflexes. Any modality of sensory input is widely distributed to a number of locations in the CNS. The pathways to and from these sites define circuits that are functionally distinct and are subject to different forms of modulation, even if there is some overlap (common inputs or cellular components) within certain sites. Therefore, clinically relevant behavioral tests of pain sensitivity for laboratory animals and humans must be sensitive to dysfunction within neural circuits to the cerebral cortex that give rise to sensations of pain. This requirement is crucial for development of a mechanism-based approach to the classification of pain [28], which often relies on techniques available only for laboratory animal studies. 5. Developing complementary strategies for animal and human pain assessment In order to match testing strategies for humans and laboratory animals, it is important to describe the varieties of hyperexcitability/increased sensitivity/unaltered
C.J. Vierck et al. / Pain 135 (2008) 7–10
sensitivity associated with each type of clinical pain. This is not as straightforward as it might seem. For example, aberrant responses to a given form of stimulation may not be demonstrable for all patients diagnosed with neuropathic pain (e.g., [15]. There are plausible reasons for this discrepancy. Even if the underlying mechanism(s) for a clinical condition were identical for all cases, which is unlikely, peripheral consequences of injury can differ over time for individuals, as can central neural plasticity in response to abnormal input. Therefore, subcategories within a pain condition should be recognized [9], and it may be instructive to determine whether a given therapeutic intervention preferentially reduces pain for any subcategory of patient defined by altered sensitivity to certain stimuli. Patients with peripheral neuropathy provide examples of considerations involved in pain sensitivity testing. Brushing the skin surface elicits pain at intensities that are positively associated with ratings of ongoing pain in subsets of patients [12,14,15]. Also, therapeutic reduction of neuropathic pain can be associated with attenuation of mechanical allodynia. These studies reinforce the value of testing somatosensory sensitivity but raise issues for translational pain research. For example, abnormal mechanical sensitivity is most reliably associated with ongoing neuropathic pain [12,14,17]. This is problematic, because mechanical stimulation is difficult to adapt to cortically dependent strategies of testing in laboratory animals. Experimenter involvement in stimulus delivery makes tests of mechanical stimulation highly susceptible to experimenter bias [2]. In order to hide (blind) mechanical stimulus delivery from behaving animals, methods of restraint are required but are difficult in a number of respects. In contrast, thermal stimulation is readily adapted to operant tests of nociceptive sensitivity in unrestrained awake animals (e.g., [11,19,20]. Psychophysical evaluation of allodynia/hyperalgesia often involves cutaneous stimulation within regions supplied by damaged nerves/pathways. For example, abnormal activity from injury to small diameter axons accounts for central sensitization to input from large afferents in the injured nerve [12], as detected by mechanical stimulation of neuropathic pain patients. However, preferential disruption of small diameter afferents can attenuate sensations elicited by thermal stimulation within the innervation territory of a damaged nerve [14]. Similarly, central lesions involving pain pathways can reduce nociceptive sensitivity for stimulation of a region with ongoing pain [1,8]. Therefore, additional evaluation of somatosensory sensitivity with stimulation outside the innervation territory of damaged nerves or pathways can be informative and should be tested in future studies. Investigations of pain sensitivity have shown that thermal allodynia/hyperalgesia is widely distributed for patients with numerous types of chronic focal pain (reviewed in [18]).
9
Operant testing of rats after constriction injury of the sciatic nerve (CCI), a well-developed model of peripheral neuropathy, reveals a prolonged hypersensitivity for cold stimulation but not heat [19]. This result is consistent with the clinical impression that cold allodynia is more common than heat allodynia in mechanical nerve injury related neuropathic pain [10,13], but reflex testing in the rat model reveals a temporary exaggeration of responses to heat. The cold hypersensitivity after CCI becomes apparent as testing trials progress, demonstrating a need for paradigms using repetitive or prolonged stimulation. Another feature in subgroups of chronic pain conditions appears to be an increased duration of elicited pain sensations [15,16], which can be expressed as after-sensations and as temporal summation of responses to repetitive stimulation. Central sensitization and temporal summation of pain are especially present during stimulation of unmyelinated nociceptors [21], and stimuli that preferentially activate C nociceptors may well be optimal for demonstrating hyperalgesia. This is particularly relevant to nociceptive heat stimulation, which can be configured to preferentially activate A-delta or C nociceptors [20]. Thus, pain patients’ sensitivities to a variety of stimulus intensities, durations, and repetition rates within and outside the distribution of their ongoing pain may characterize specific pain conditions in a manner that can be tested in animal studies. 6. Conclusions Pain is not a reflex. It is a perceptual experience with powerful emotional and motivational components. Like all sensory systems, attributes of pain such as intensity, quality, duration, location, and extent depend upon cerebral processing. This applies to both laboratory animals and humans. Because chronic pain necessarily results from abnormal activity in pain transmission systems, perturbing a hyperactive/hypersensitive pain pathway with stimulation should have the potential to reveal some form of allodynia/hyperalgesia for all pain conditions. The optimal forms of stimulation and the spatial distribution of hypersensitivity are likely to vary between pain conditions. These differences should be thoroughly described in humans so they can be utilized in animal models of presumed chronic pain. Successful testing of therapies for chronic pain depends upon coordination of procedures used in both animal and human studies. This approach can be expected to greatly improve discovery of therapeutic agents and the development of successful remedies for chronic pain.
References [1] Boivie J. Central pain and the role of quantitative sensory testing (QST) in research and diagnosis. Europ J Pain 2003;7:339–43.
10
C.J. Vierck et al. / Pain 135 (2008) 7–10
[2] Chesler E, Wilson S, Lariviere W, Rodriguez-Zas S, Mogil J. Influences of laboratory environment on behavior. Nat Neurosci 2002;5:1101–2. [3] Coghill R, Morrow T. Functional imaging of animal models of pain: high-resolution insights into nociceptive processing. In: Casey K, Bushnell M, editors. Pain imaging, progress in pain research and management. Seattle: IASP Press; 2000. p. 211–39. [4] Cooper BY, Vierck Jr CJ. Vocalizations as measures of pain in monkeys. Pain 1986;26:393–408. [5] Craggs JG, Price DD, Verne GN, Perlstein WM, Robinson MM. Functional brain interactions that serve cognitive–affective processing during pain and placebo analgesia. Neuroimage 2007;38:720–9. [6] Davis K. Studies of pain using functional magnetic resonance imaging. In: Casey K, Bushnell M, editors. Pain imaging; progress in pain research and management. Seattle: IASP Press; 2000. p. 195–210. [7] Davis M, Zautry A, Reich J. Vulnerability to stress among women in chronic pain from fibromyalgia and osteoarthritis. Ann Behav Med 2001;23:215–26. [8] Finnerup NB, Sørensen L, Biering-Sørensen F, Johannesen IL, Jensen TS. Segmental hypersensitivity and spinothalamic function in spinal cord injury pain. Exp Neurol 2007;207:139–49. [9] Hansson P. Difficulties in stratifying neuropathic pain by mechanisms. Europ J Pain 2003;7:353–7. [10] Jorum E, Warncke T, Stubhaug A. Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist Ketamine – a double-blind crossover comparison with alfentanil and placebo. Pain 2003;101:229–35. [11] King C, Devine D, Vierck C, Mauderli A, Yezierski R. Opioid modulation of reflex versus operant responses following stress in the rat. Neuroscience 2007;147:174–82. [12] Koltzenburg M, Torebjo¨rk J, Wahren L. Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain 1994;117:579–91. [13] Leffler A-S, Hansson P. Painful traumatic peripheral partial nerve injury–sensory dysfunction profiles comparing outcomes of bedside examination and quantitative sensory testing. Eur J Pain, Epub ahead of print. [14] Rowbotham M, Fields H. The relationship of pain, allodynia and thermal sensation in post-herpetic neuralgia. Brain 1996;119:347–54. [15] Samuelsson M, Leffler A-S, Hansson P. Dynamic mechanical allodynia: On the relationship between temporo-spatial stimulus parameters and evoked pain in patients with peripheral neuropathy. Pain 2005;115:264–72.
[16] Staud R, Price DD, Robinson ME, Mauderli AP, Vierck CJ. Maintenance of windup of second pain requires less frequent stimulation in fibromyalgia patients compared to normal controls. Pain 2004;110:689–96. [17] Verdugo R, Ochoa J. Quantitative somatosensory thermotest. A key method for functional evaluation of small calibre afferent channels. Brain 1992;115:893–913. [18] Vierck C. Mechanisms underlying development of spatially distributed chronic pain (fibromyalgia). Pain 2006;124:242–63. [19] Vierck C, Acosta-Rua A, Johnson R. Bilateral chronic constriction of the sciatic nerve:a model of long-term cold hyperalgesia. J Pain 2005;6:507–17. [20] Vierck C, Acosta-Rua A, Nelligan R, Tester N, Mauderli A. Low dose systemic morphine attenuates operant escape but facilitates innate reflex responses to thermal stimulation. J Pain 2002;3:309–19. [21] Vierck CJ, Cannon R, Fry G, Maixner W, Whitsel B. Characteristics of temporal summation of second pain sensations elicited by brief contact of glabrous skin by a preheated thermode. J Neurophysiol 1997;78:992–1002. [22] Vierck CJ, Greenspan JD, Ritz LA. Long term changes in purposive and reflexive responses to nociceptive stimulation in monkeys following anterolateral chordotomy. J Neurosci 1990;10:2077–95. [23] Vierck CJ, Kline R, Wiley RG. Intrathecal substance P-saporin attenuates operant escape from nociceptive thermal stimuli. Neuroscience 2003;119:223–32. [24] Vierck CJ, Kline RL, Wiley RG. Comparison of operant escape and innate reflex responses to nociceptive skin temperatures produced by heat and cold stimulation of rats. Behav Neurosci 2004;118:627–35. [25] Vincler MO, Maixner W, Vierck Jr CJ, Light AR. Estrous cycle modulation of nociceptive behaviors elicited by electrical stimulation and formalin. Pharmacol Biochem Behav 2001;69:315–24. [26] Vierck CJ, Light AR. Effects of combined hemotoxic and anterolateral spinal lesions on nociceptive sensitivity. Pain 1999;83:447–57. [27] Wiley RG, Kline RL, Vierck CJ. Anti-nociceptive effects of selectively destroying substance P receptor-expressing dorsal horn neurons using [Sar9,Met(O2)11] substance P-saporin: behavioral and anatomical analysis. Neuroscience 2007;146:1333–45. [28] Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R, et al. Towards a mechanism-based classification of pain? Pain 1998;77:227–9. [29] Yeomans DC, Cooper BY, Vierck CJ. Effects of systemic morphine on responses to first or second pain sensations of primates. Pain 1996;66:253–63.
Topical review
Clinical and pre-clinical pain assessment: Are we measuring the same thing? C.J. Vierck
a,*
, P.T. Hansson c, R.P. Yezierski
b
a
Department of Neuroscience, College of Medicine, Comprehensive Center for Pain Research, University of Florida, 200 Newell Drive, McKnight Brain Institute, Gainesville, FL, USA b Department of Orthodontics, College of Dentistry, Comprehensive Center for Pain Research, University of Florida, Gainesville, FL, USA c Department of Molecular Medicine and Surgery, Section of Clinical Pain Research, Karolinska Institutet and Department of Neurosurgery, Pain Center, Karolinska University Hospital, Stockholm, Sweden Received 4 December 2007; received in revised form 14 December 2007; accepted 18 December 2007
1. Introduction Assessment of clinical pain presents a unique problem compared to other major health conditions, such as heart disease or cancer, which can be detected by objective biological measurements. Diagnosis of chronic pain depends upon subjective reports by patients on the presence and intensity of pain. However, comparable reports on sensory attributes cannot be obtained from laboratory animals without language skills. Nevertheless, attempts to assess chronic pain in non-human species have involved observations of spontaneous behavioral or physiological reactions to presumed sources of pain. Unfortunately, spontaneous events such as vocalizations, autotomy/overgrooming, sleep disruption or autonomic activation do not qualify as direct measures of pain. When autotomy or overgrooming occurs, the eliciting stimulus is unknown – it could be numbness with analgesia or a non-painful paresthesia. Autotomy and grooming are not always associated with pain, and either can be assumed to exist in the absence of pain. Sleep disruption and autonomic dysregulation can be associated with and can exacerbate chronic pain [7], but neither results only from chronic pain. If sleep disruption were to be used as a primary measure of pain for development of analgesics, an effective compound might act directly on circuits regulating sleep cycles but have no effect on pain. Similarly, low dose systemic morphine directly attenuates *
Corresponding author. Tel./fax: +1 352 371 2378. E-mail address: [email protected]fl.edu (C.J. Vierck).
vocalizations of animals performing a food reinforcement task in the absence of any nociceptive stimulation [4]. Morphine reduces pain sensitivity, but this conclusion is not justified on the basis of an effect on vocalizations. Therefore, spontaneous behavioral or physiological events can complement but not replace direct measurements of pain or pain sensitivity. 2. Assessment of pain sensitivity of human and laboratory animal subjects In the present article, efforts are made to relate assessment of pain in human and laboratory animal subjects. The use of comparable methods in pre-clinical and clinical studies is critical to successful translational research. In this effort, assessment of pain sensitivity can be approached similarly with behavioral observations of humans and laboratory animals. Altered sensitivities of humans to somatosensory stimulation can validate ratings of ongoing pain, and for some conditions (e.g., fibromyalgia) diagnostic procedures include ratings of sensations generated by applied stimuli. Stimulus– response functions for escape from nociceptive stimulation can provide comparable information for laboratory animals. For both humans and laboratory animals, two principals are critical for evaluation of pain sensitivity. Measures of pain must: (1) reveal transmission over nociceptive pathways that extend to the cerebral cortex; and (2) require processing of sensory intensity in comparison with previous pain experiences. Importantly,
0304-3959/$32.00 Ó 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2007.12.008
8
C.J. Vierck et al. / Pain 135 (2008) 7–10
evaluation and reporting of pain intensity cannot occur without prior learning by either humans or laboratory animals. However, pain research with laboratory animals has relied historically upon observations of innate reflex responses that do not require cerebral processing of sensory intensity and are not dependent upon experience (learning). Reflex responses result from activation and modulation of spinal and supraspinal circuits that are distinct from pain transmission pathways from the periphery to cerebral sites mediating sensory, emotional, and motivational reactions to pain. Evidence from human imaging studies shows that cerebral cortical structures participate in the conscious perception of pain [6]. Also, functional labeling of the brain in response to nociceptive stimulation of laboratory animals supports the importance of cortical processing in pre-clinical models of pain [3]. Further demonstrating an essential contribution of high order processing are repeated validations of assessment instruments (e.g., McGill Pain Questionnaire) that emphasize cortically dependent psychosocial components of the pain experience. Therefore, it is imperative that assessments of pain in laboratory animals quantify behavioral responses to sensory experiences that are cortically mediated. Otherwise, behavioral assessment cannot provide a basis for delineation of fundamental mechanisms or identification of therapeutic targets or decisions regarding drug discovery and evaluation. If we are not getting the right answers with behavioral assessment there is no way we are going to succeed with translation from preclinical to clinical trials of therapeutic efficacy. 3. Evaluation of pain sensitivity in laboratory animals Consequent to appearance of the gate-control theory, there was excitement that nociceptive transmission could be controlled at synaptic relays in the spinal dorsal horn. Reflex tests have been used almost exclusively to reveal these effects on nociceptive transmission in waking animals. However, to show the relevance of reflex modulation to supraspinal pain processing, spinothalamic projection neurons must be affected identically to motoneurons in reflex circuits. Recordings from spinothalamic cells and motoneurons have rarely been compared directly and are necessarily obtained from preparations with unknown combinations of nociceptive inhibition and facilitation from anesthesia and surgical dissection. Furthermore, modern imaging studies have demonstrated that pain experiences are not dictated entirely by activity of spinothalamic neurons [5]. When direct comparisons have been made between reflex responses and cortically dependent operant escape tests, consistently different, sometimes opposite, effects have been demonstrated. For normal animals, stimulus– response functions for reflex and escape responses differ for heat, cold, and electrical stimulation, as do effects of
age, gender and the estrus cycle (e.g., [24,25]). A variety of experimental manipulations differentially affect reflex and escape responses; these include: morphine, naloxone, stress, morphine plus stress, naloxone plus stress, subcutaneous formalin injection, cutaneous application of mustard oil, chronic constrictive nerve injury, spinal white matter lesions (dorsolateral column, dorsal quadrant, anterolateral column, lateral hemisection), injury to spinal gray matter (quisqualic acid and selective neurotoxins SP-sap and SSP-sap), and i.p. or intrathecal injection of icilin (e.g., [11,19,20,22,23,26,27,29]). In these studies, operant effects have been consistent with expectations from human studies, but reflex effects have not. This is not to say that reflex testing has no utility in pain research. For example, the actions of opiates on spinal circuits were originally characterized with reflex tests. However, it is now apparent that complete reliance on reflex methods is not advisable, and reflex modulation cannot be equated with pain modulation. 4. Are reflex measures useful in translation of animal studies to humans? The use of reflex measures has been dictated by an interest in efficiency, but should speed of data collection be the primary consideration in selecting behavioral measures? Obtaining misleading results is the epitome of inefficiency. For example, pharmacologists would not attempt to understand mechanisms of action at receptor A with agonists or antagonists that bind to receptor B. This analogy applies to actions on reflexes (circuit B) which purport to reveal effects on pain (circuit A). Similarly, few would contend that visual sensations could be modeled by studying the pupillary light reflex or that conscious auditory experience can be revealed by studying startle or cephalogyric reflexes. Any modality of sensory input is widely distributed to a number of locations in the CNS. The pathways to and from these sites define circuits that are functionally distinct and are subject to different forms of modulation, even if there is some overlap (common inputs or cellular components) within certain sites. Therefore, clinically relevant behavioral tests of pain sensitivity for laboratory animals and humans must be sensitive to dysfunction within neural circuits to the cerebral cortex that give rise to sensations of pain. This requirement is crucial for development of a mechanism-based approach to the classification of pain [28], which often relies on techniques available only for laboratory animal studies. 5. Developing complementary strategies for animal and human pain assessment In order to match testing strategies for humans and laboratory animals, it is important to describe the varieties of hyperexcitability/increased sensitivity/unaltered
C.J. Vierck et al. / Pain 135 (2008) 7–10
sensitivity associated with each type of clinical pain. This is not as straightforward as it might seem. For example, aberrant responses to a given form of stimulation may not be demonstrable for all patients diagnosed with neuropathic pain (e.g., [15]. There are plausible reasons for this discrepancy. Even if the underlying mechanism(s) for a clinical condition were identical for all cases, which is unlikely, peripheral consequences of injury can differ over time for individuals, as can central neural plasticity in response to abnormal input. Therefore, subcategories within a pain condition should be recognized [9], and it may be instructive to determine whether a given therapeutic intervention preferentially reduces pain for any subcategory of patient defined by altered sensitivity to certain stimuli. Patients with peripheral neuropathy provide examples of considerations involved in pain sensitivity testing. Brushing the skin surface elicits pain at intensities that are positively associated with ratings of ongoing pain in subsets of patients [12,14,15]. Also, therapeutic reduction of neuropathic pain can be associated with attenuation of mechanical allodynia. These studies reinforce the value of testing somatosensory sensitivity but raise issues for translational pain research. For example, abnormal mechanical sensitivity is most reliably associated with ongoing neuropathic pain [12,14,17]. This is problematic, because mechanical stimulation is difficult to adapt to cortically dependent strategies of testing in laboratory animals. Experimenter involvement in stimulus delivery makes tests of mechanical stimulation highly susceptible to experimenter bias [2]. In order to hide (blind) mechanical stimulus delivery from behaving animals, methods of restraint are required but are difficult in a number of respects. In contrast, thermal stimulation is readily adapted to operant tests of nociceptive sensitivity in unrestrained awake animals (e.g., [11,19,20]. Psychophysical evaluation of allodynia/hyperalgesia often involves cutaneous stimulation within regions supplied by damaged nerves/pathways. For example, abnormal activity from injury to small diameter axons accounts for central sensitization to input from large afferents in the injured nerve [12], as detected by mechanical stimulation of neuropathic pain patients. However, preferential disruption of small diameter afferents can attenuate sensations elicited by thermal stimulation within the innervation territory of a damaged nerve [14]. Similarly, central lesions involving pain pathways can reduce nociceptive sensitivity for stimulation of a region with ongoing pain [1,8]. Therefore, additional evaluation of somatosensory sensitivity with stimulation outside the innervation territory of damaged nerves or pathways can be informative and should be tested in future studies. Investigations of pain sensitivity have shown that thermal allodynia/hyperalgesia is widely distributed for patients with numerous types of chronic focal pain (reviewed in [18]).
9
Operant testing of rats after constriction injury of the sciatic nerve (CCI), a well-developed model of peripheral neuropathy, reveals a prolonged hypersensitivity for cold stimulation but not heat [19]. This result is consistent with the clinical impression that cold allodynia is more common than heat allodynia in mechanical nerve injury related neuropathic pain [10,13], but reflex testing in the rat model reveals a temporary exaggeration of responses to heat. The cold hypersensitivity after CCI becomes apparent as testing trials progress, demonstrating a need for paradigms using repetitive or prolonged stimulation. Another feature in subgroups of chronic pain conditions appears to be an increased duration of elicited pain sensations [15,16], which can be expressed as after-sensations and as temporal summation of responses to repetitive stimulation. Central sensitization and temporal summation of pain are especially present during stimulation of unmyelinated nociceptors [21], and stimuli that preferentially activate C nociceptors may well be optimal for demonstrating hyperalgesia. This is particularly relevant to nociceptive heat stimulation, which can be configured to preferentially activate A-delta or C nociceptors [20]. Thus, pain patients’ sensitivities to a variety of stimulus intensities, durations, and repetition rates within and outside the distribution of their ongoing pain may characterize specific pain conditions in a manner that can be tested in animal studies. 6. Conclusions Pain is not a reflex. It is a perceptual experience with powerful emotional and motivational components. Like all sensory systems, attributes of pain such as intensity, quality, duration, location, and extent depend upon cerebral processing. This applies to both laboratory animals and humans. Because chronic pain necessarily results from abnormal activity in pain transmission systems, perturbing a hyperactive/hypersensitive pain pathway with stimulation should have the potential to reveal some form of allodynia/hyperalgesia for all pain conditions. The optimal forms of stimulation and the spatial distribution of hypersensitivity are likely to vary between pain conditions. These differences should be thoroughly described in humans so they can be utilized in animal models of presumed chronic pain. Successful testing of therapies for chronic pain depends upon coordination of procedures used in both animal and human studies. This approach can be expected to greatly improve discovery of therapeutic agents and the development of successful remedies for chronic pain.
References [1] Boivie J. Central pain and the role of quantitative sensory testing (QST) in research and diagnosis. Europ J Pain 2003;7:339–43.
10
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[2] Chesler E, Wilson S, Lariviere W, Rodriguez-Zas S, Mogil J. Influences of laboratory environment on behavior. Nat Neurosci 2002;5:1101–2. [3] Coghill R, Morrow T. Functional imaging of animal models of pain: high-resolution insights into nociceptive processing. In: Casey K, Bushnell M, editors. Pain imaging, progress in pain research and management. Seattle: IASP Press; 2000. p. 211–39. [4] Cooper BY, Vierck Jr CJ. Vocalizations as measures of pain in monkeys. Pain 1986;26:393–408. [5] Craggs JG, Price DD, Verne GN, Perlstein WM, Robinson MM. Functional brain interactions that serve cognitive–affective processing during pain and placebo analgesia. Neuroimage 2007;38:720–9. [6] Davis K. Studies of pain using functional magnetic resonance imaging. In: Casey K, Bushnell M, editors. Pain imaging; progress in pain research and management. Seattle: IASP Press; 2000. p. 195–210. [7] Davis M, Zautry A, Reich J. Vulnerability to stress among women in chronic pain from fibromyalgia and osteoarthritis. Ann Behav Med 2001;23:215–26. [8] Finnerup NB, Sørensen L, Biering-Sørensen F, Johannesen IL, Jensen TS. Segmental hypersensitivity and spinothalamic function in spinal cord injury pain. Exp Neurol 2007;207:139–49. [9] Hansson P. Difficulties in stratifying neuropathic pain by mechanisms. Europ J Pain 2003;7:353–7. [10] Jorum E, Warncke T, Stubhaug A. Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist Ketamine – a double-blind crossover comparison with alfentanil and placebo. Pain 2003;101:229–35. [11] King C, Devine D, Vierck C, Mauderli A, Yezierski R. Opioid modulation of reflex versus operant responses following stress in the rat. Neuroscience 2007;147:174–82. [12] Koltzenburg M, Torebjo¨rk J, Wahren L. Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain 1994;117:579–91. [13] Leffler A-S, Hansson P. Painful traumatic peripheral partial nerve injury–sensory dysfunction profiles comparing outcomes of bedside examination and quantitative sensory testing. Eur J Pain, Epub ahead of print. [14] Rowbotham M, Fields H. The relationship of pain, allodynia and thermal sensation in post-herpetic neuralgia. Brain 1996;119:347–54. [15] Samuelsson M, Leffler A-S, Hansson P. Dynamic mechanical allodynia: On the relationship between temporo-spatial stimulus parameters and evoked pain in patients with peripheral neuropathy. Pain 2005;115:264–72.
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