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American Pain Society
4700 W Lake Ave
Glenview, IL 60025
Norman Harden, MD, Department Editor
Robert P. Yezierski, PhD, and Charles J. Vierck, PhD
The current status of preclinical pain research dictates that we assess strategies used to unravel mechanisms, identify therapeutic targets, develop novel treatment strategies, and evaluate efficacy of new compounds. This seems especially important in light of a rather disappointing track record for translation of basic research findings to bedside applications. Is this a commentary on the effectiveness of our current system of drug discovery, or is it the reality of combating challenging clinical conditions? Perhaps the underlying message is that we should be looking for a paradigm shift in our strategy of drug discovery to achieve a better return on the significant financial investment by academic, industrial, and governmental institutions. At the center of the goals we are trying to achieve is one thing that has remained constant for more than 20 years—the methods we use to assess pain in the preclinical setting. If we are to move forward, it is essential to dissect the behavioral strategies (along with different pain models) currently in use and critically appraise their clinical relevance and predictive value.
| “If the behavioral measures we are using are not providing the right answers, we have little chance of succeeding with the translation of preclinical studies to clinical trials of therapeutic efficacy.” |
Pain presents a unique problem compared to other major health conditions, such as heart disease or cancer, both of which can be detected by objective biological measurements. Diagnosis of chronic pain suffered by humans depends on subjective reports related to the presence and intensity of pain. Unfortunately, comparable reports related to ongoing pain cannot be obtained from laboratory animals. The best we can do is compare responses of animals and ratings of humans to elicited pain (Vierck et al., 2008b). Because chronic pain necessarily results from abnormal activity in pain transmission systems, perturbing a hyperactive/hypersensitive pain pathway with stimulation should reveal some form of allodynia/hyperalgesia for all chronic pain conditions. The optimal forms of stimulation and the spatial distribution of hypersensitivity are likely to vary between pain conditions. These differences should be described thoroughly in humans and paralleled by behavioral endpoints used in putative animal models of chronic pain.
For both humans and laboratory animals, two principles are critical for evaluation of pain sensitivity: (a) pain measures must reveal transmission over nociceptive pathways that extend to the cerebral cortex for processing; and (b) pain reports require comparisons of current sensory intensity with previous pain experiences. Evaluation and reporting of pain intensity cannot occur without prior learning. However, pain research involving laboratory animals historically has relied on observations of reflex responses that do not require cerebral processing and are not dependent on experience (learning). Reflex responses result from activation of spinal-brain stem-spinal circuits that are uniquely modulated and are distinct from pain transmission pathways from the periphery to cerebral substrates mediating sensory, emotional, and motivational reactions to pain.
In the evaluation of pain assessment strategies it is important to acknowledge that human imaging studies show involvement of cortical structures involved in the conscious perception of pain and associated emotional reactions (Davis 2000; Craggs et al. 2007). Also, functional labeling of the brain in response to nociceptive stimulation of laboratory animals supports the importance of cortical processing in preclinical models of pain (Coghill & Morrow, 2000). For these reasons, assessment of preprogrammed reflexes that can be performed by decerebrate or spinalized animals does not qualify and can be highly misleading. If the behavioral measures we are using are not providing the right answers, we have little chance of succeeding with the translation of preclinical studies to clinical trials of therapeutic efficacy.
An important exercise in the evaluation of pain assessment strategies is direct comparison of different methods. Such comparisons between simple reflex responses and cortically-dependent operant escape tests consistently have yielded different and sometimes opposite effects. In the case of 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 (Vincler et al., 2001; Vierck et al., 2004, 2008a). Furthermore, numerous experimental manipulations differentially affect reflex and escape responses, including: systemic morphine or naloxone, stress, morphine plus stress, naloxone plus stress, subcutaneous formalin, cutaneous 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 systemic icilin (Vierck et al., 1990; 2002, 2003, 2005, 2008c; Yeomans et al., 1996; Vierck & Light, 1999; King et al., 2007; Wiley et al., 2007). In these studies, operant but not reflex effects have been consistent with expectations for humans, thus providing validation for the use of cortically dependent operant measures.
Different effects of experimental manipulations on operant and reflex responses have important implications for preclinical assessment. Thousands of pharmacological agents have been screened for analgesic effects with reflex methods that impose a high probability of false negatives and false positives. For example, if systemic morphine initially had been screened for analgesic properties with reflex methods in rats, without knowledge of its effects on human pain, it would have been rejected. Considering the standard strategy for drug testing is increasing the dose of an agent until a reflex effect is obtained, it is important to point out that low dose systemic morphine produces hyperreflexia (King et al., 2007; Vierck et al, 2002). Given the clinical evidence from humans, we acknowledge this is a false-negative result! The same low doses of morphine produce the expected analgesic result and reduce operant responding of rats to the same stimuli (hypoalgesia). High doses of morphine are sedative and depress motoneuronal excitability, and the resultant hyporeflexia (a false positive) cannot be attributed to sensory modulation.
Another example of how the pain field has ascribed a clinical characteristic of pain (analgesia) to a motor phenomenon (hyporeflexia) is the effect of psychological stress on nociceptive reflexes. An enormous number of animal studies consistently have generated false-positive results of considerable clinical importance to translational pain research. These studies have characterized the suppression of reflex responses by different stressors in what has been referred to as “stress-induced analgesia.” In contrast to reflex suppression, operant escape testing reveals hyperalgesia for a stressor that attenuates reflex responses to the same nociceptive stimuli (King et al., 2007). Stress-induced hyperalgesia is consistent with the clinical experience that stress can lead to development of chronic pain (Vierck, 2006), which is a stressor, setting up a positive feedback loop (Davis et al., 2001). Consequently, reflex testing would not support a pharmacological initiative to screen drugs that control stress effects on chronic pain.
The use of reflex measures has been greatly dictated by efficiency. However, obtaining misleading results is worse than inefficient. It is counterproductive, and therefore speed of data collection should never be the primary consideration in selecting behavioral measures. The fallacy of using reflex measures to test a sensory attribute becomes obvious if one considers this strategy for other sensory modalities. Few would contend that visual sensations can be modeled by studying the pupillary light reflex or that conscious auditory experiences can be revealed by studying startle or cephalogyric reflexes. It should be apparent that reliance on reflex tests of nociception is not advisable, and reflex modulation cannot be equated with pain modulation.
Based on the International Association for the Study of Pain definition, pain is not a reflex—it is a perceptual experience with powerful emotional and motivational components. As for all sensory systems, attributes of pain such as intensity, quality, duration, location, and extent depend on cerebral processing. This applies to both laboratory animals and humans. Successful testing of therapies for chronic pain depends on coordination of procedures that appropriately evaluate pain sensitivity in laboratory animal and human studies. This strategy can be expected to greatly improve discovery of therapeutic agents and development of successful remedies for chronic pain. The importance of finding clinically relevant and predictive measures of behavioral assessment is critical to achieving success in the arena of translational research. If we have not achieved success that justifies the investment of time, money, and effort, and if we don’t want to repeat mistakes of the past, the only reasonable option is to change our approach.
Coghill, R., Morrow, T. (2000). Functional imaging of animal models of pain: high-resolution insights into nociceptive processing. In K.L. Casey & M.C. Bushnell (Eds.), Pain Imaging: Progress in Pain Research and Management (pp. 211-239). Seattle: IASP Press.
Craggs, J.G., Price, D.D., Verne, G.N., Perlstein, W.M., Robinson, M.M. (2007). Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia. Neuroimage, 38, 720-729.
Davis, K. (2000). Studies of pain using functional magnetic resonance imaging. In K.L. Casey & M.C. Bushnell (Eds.), Pain Imaging: Progress in Pain Research and Management (pp. 195-210). Seattle: IASP Press.
Davis, M., Zautry A., Reich J. (2001). Vulnerability to stress among women in chronic pain from fibromyalgia and osteoarthritis. Ann Behav Med, 23, 215-226.
King, C., Devine D., Vierck C., Mauderli A., Yezierski R. (2007). Opioid modulation of reflex versus operant responses following stress in the rat. Neurosci 147, 174-182.
Vierck, C. (2006). Mechanisms underlying development of spatially distributed chronic pain (fibromyalgia). Pain, 124, 242-263.
Vierck, C., Acosta-Rua, A., Johnson, R. (2005). Bilateral chronic constriction of the sciatic nerve: A model of long-term cold hyperalgesia. J Pain, 6, 507-517.
Vierck, C., Acosta-Rua, A., Nelligan, R., Tester, N., Mauderli, A. (2002). Low dose systemic morphine attenuates operant escape but facilitates innate reflex responses to thermal stimulation. J Pain 3, 309-319.
Vierck, C., Acosta-Rua, A.J., Rossi, H.L., Neubert, J.K. (2008a). Sex differences in thermal pain sensitivity and sympathetic reactivity for two strains of rat. J Pain.
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Vierck, C.J., Hansson, P.T., Yezierski, R.P. (2008b). Clinical and pre-clinical pain assessment: Are we measuring the same thing? Pain, 135, 7-10.
Vierck, C.J., Kline, R., Wiley, R.G. (2003). Intrathecal substance P-saporin attenuates operant escape from nociceptive thermal stimuli. J Neurosci, 119, 223-232.
Vierck, C.J., Kline, R.L.,Wiley, R.G. (2004) Comparison of operant escape and innate reflex responses to nociceptive skin temperatures produced by heat and cold stimulation of rats. Behav Neurosci, 118, 627-635.
Vierck, C.J., Light, A.R. (1999). Effects of combined hemotoxic and anterolateral spinal lesions on nociceptive sensitivity. Pain, 83, 447-457.
Vierck, C.J., Yezierski, R.P., Light, A.R. (2008c). Long-lasting hyperalgesia and sympathetic dysregulation after formalin injection into the rat hindpaw. Neurosci 153, 501-506.
Vincler, M., Maixner, W., Vierck, C.J., Light, A.R. (2001). Estrous cycle modulation of nociceptive behaviors elicited by electrical stimulation and formalin. Pharmacol Biochem Behav, 69, 315-324.
Wiley, R.G., Kline, R.L., Vierck, C.J. (2007). 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. Neurosci 146, 1333-1345.
Yeomans, D.C., Cooper, B.Y., Vierck, C.J. (1996). Effects of systemic morphine on responses to first or second pain sensations of primates. Pain 66, 253-263
Robert Yezierski, PhD, is the director and a professor in the Department of Orthodontics, College of Dentistry, Comprehensive Center for Pain Research, University of Florida, Gainesville, FL. Charles Vierck, PhD, also is a professor in the Department of Orthodontics, College of Dentistry, Comprehensive Center for Pain Research, University of Florida, Gainesville, FL.
