Andre P. Mauderli - US grants

The overall goal of this research is to enhance our understanding of how the aversive quality of pain is represented in the brain. Clinicians would welcome better methods for selectively reducing the unpleasantness of pain, while preserving other aspects of the sensation. Clinical, anatomical and physiological evidence speaks for a role of the thalamus in the conscious appreciation of pain. Nociceptive input is distributed to a variety of telencephalic targets from a number of thalamic nuclei, which represent nodes in a complex network of sensory, motor and limbic interactions. This research will provide a better insight into the function if diencephalic nociceptive systems and thus will aid in the development of treatments for presently intractable pain conditions. This proposal focuses on three diencephalic regions for which existing knowledge suggests a role in affective aspects of pain and/or related behaviors: the zona incerta, the nucleus submedius and the center median/parafascicular complex. The general approach is to measure the effect of bilateral stereotaxic radiofrequency lesions on operant behaviors elicited by nociceptive (heat) and non-nociceptive (bright light) aversive stimuli in the rat, in order to discriminate between different potential consequences of these lesions. The proposed behavioral assays are using different stimuli to elicit the same motor behavior, in order to differentiate between specific effects on nociception, generalized effects on aversion and motor effects. The tests further allow comparisons between effects on consciously perceived pain sensations (inferred from consciously directed learned escape behaviors) and more primitive, possible reflexive responses, such as hindpaw-licking. Proposed methodological refinements in the stereotaxic lesioning technique are expected to limit the extent of thalamic damage: 1.) corrections of stereotaxic errors due to inter-subject variability are made after surveying skeletal landmarks; 2.) the radiofrequency lesions are temperature-feedback controlled for achieving a predictable lesion size. Better focused and reproducible lesions facilitate greatly the interpretation of the resulting behavioral deficits.

DESCRIPTION (provided by the applicant): Prolonged pain appears to have the potential to modulate its own intensity through positive and negative feedback (central sensitization by pain, pain inhibition by pain). If the feedback is positive, the result is a vicious pain cycle and a progressive increase in pain sensitivity. Increased pain sensitivity means that a given stimulus is perceived as more painful (hyperalgesia), or - in more extreme cases - that a previously non-painful stimulus becomes painful (allodynia). The vicious cycle may lead to sensitization beyond the topographical boundaries of the original pain, and thus it may render remote body regions more pain-prone. The result may be a snowball effect of progressive expansion of the painful area. There is evidence suggesting that the vicious cycle may be a pathophysiological factor in certain chronic pain diseases, including fibromyalgia syndrome (FMS), myofascial pain syndrome (MPS), and irritable bowel syndrome (IBS). This research is guided by 4 questions: 1) Does the intensity and duration of a persistent pain have an effect on how pain sensitivity changes over time? 2) Does the sensitizing effect of pain signals reach beyond the topographical location of the original pain focus? 3) Is it possible to interrupt the vicious pain cycle and allow the sensitized state to return to normal by temporarily silencing the local pain focus that presumably started the cycle? 4) Does the maintenance of the sensitized state depend on central NMDA receptor function, molecular constituents known to play a role in temporal integration of pain stimuli and other memory systems? The subjects in this study will be asked to rate pain intensities by setting the slider on an electronic visual analog scale. Novel methodology will be used for probing the temporal and spatial response properties of central pain modulation with experimental pain with prolonged series of thermal pulses. The effect of silencing clinical pain foci with transdermally delivered local anesthetics on thermallyinduced sensitization will be studied. The importance of NMDA receptor systems in the maintenance of a sensitized state will be assessed by measuring pain sensitization properties before and after pharmacologically blocking them.

[unreadable] DESCRIPTION (provided by applicant): The goal of the project is to build and test prototypes for a research tool for investigating pain mechanisms and for screening prospective new pain-relieving drugs for their effect. The system consists of hardware and software designed to measure thermal pain sensitivity of rodents (rats and mice) based upon learned (cortically mediated) escape behaviors that are induced by thermal stimuli (hot or cold) to the paws. The apparatus features a testing chamber with two temperature-controlled floor areas (one typically at a painful temperature, the other thermally neutral). The delay with which the animal escapes from the painful to the neutral area is the measured response. After each escape the animal is motivated to return to the stimulus surface by turning on a bright light (bright light is aversive to rodents and they will escape it). This allows conducting multiple escape trials in an automated manner without the need for handling the animal between trials. The system includes a control test for measuring effects on the escape response that are not pain-related. A major advantage over existing pain tests is that the measured escape responses can be elicited by moderate stimulus intensities and serve as a model of human clinical pain that depends on temporal integration of nociceptive signals. The new method provides the scientist and drug developer with a methodological alternative that takes into account the contribution of higher level pain processing to a much larger degree than traditional reflex-based rodent pain tests. The method therefore extends the range of tests that are possible with animals and reduces the need for potentially risky and more expensive human experiments. The new test is more humane and less stressful than traditional reflex-based tests because the animals are not restrained, not in contact with humans during the test and in full control over stimulus onset and end. This project will refine the hardware and software of the new thermal operant pain sensitivity test to the point that it is a reliable, flexible and user-friendly tool for investigators that is commercially marketable. [unreadable] [unreadable] [unreadable]