James N. Campbell - US grants

The long range objective of this research is to use neurophysiological and psychophysical techniques to develop a better understanding of pain perception. In this grant we propose to continue studies of peripheral neural mechanisms of pain sensation. Chronic pain often results from injury to the peripheral nerve, and thus results of these studies may have direct relevance to the treatment of chronic pain. An important strategy of this research is to correlate the response of primary nociceptive afferents, obtained from single fiber recordings in the monkey, with the response of human subjects, based on ratings of subjective magnitude, when both are exposed to the same stimuli. The specific goals are: (1) to characterize further the normal response properties of primary nociceptive afferents in order to understand better the peripheral neural coding mechanisms for thermal and mechanical pain perception, (2) to continue research on the neural mechanisms of primary and secondary hyperalgesia induced by cutaneous injury and (3) to continue neurophysiological and psychophysical studies of peripheral nerve injury.

We determined in preliminary studies that the responses to cutaneous heat stimuli of nociceptive primary afferents in the monkey were substantially affected by the choice of anesthetic. These results challenge the commonly held assumption that general anesthetics do not alter the response of primary afferents. The purpose of this proposed research is to characterize further the effect of anesthetics on the response properties of primary somatosensory afferents. A major objective will be to determine which anesthetic has the least effect on the responses of nociceptive afferents and thus can be used to model the awake animal in neurophysiological studies. Using single fiber recording techniques, we will examine the responses of nociceptive afferents not only to heat but also to mechanical stimuli. We will also determine if other types of primary afferents including slowly and quickly adapting low-threshold mechanoreceptive afferents, warm fibers, and cold fibers are affected by anesthetics. Finally, we will determine if ancillary factors such as blood pressure, core and skin temperature, sympathetic tone, and acid-base balance contribute to the anesthetic effect. This research is fundamental to advancing knowledge of the somatosensory system, and in particular pain sensation. This research may also provide further clues as to the mechanism by which anesthetics affect the nervous system.

The objective of this proposal is to foster a multidisciplinary approach for the study of neuropathic pain. The integration of different but related strategies provided by this program will result in greater scientific contributions than if each project were pursued individually. This proposal will bring together the disciplines of electrophysiology, pharmacology, and clinical trials research to investigate the mechanisms and treatment of neuropathic pain. Project I is directed at understanding thalamic mechanisms of pain sensation by examining the neural activity of cells (as well as the effects of electrical microstimulation) in the human thalamus of patients with chronic pain and those with normal sensory function. Project II examines properties of projection cells from the dorsal horn to the brainstem and hypothalamus. The focus is to determine the role of excitatory amino acids and neurokinins in production of hyperalgesia, a common sensory abnormality in neuropathic pain. Project III is directed at understanding the pathophysiology and biochemical nature of sympathetically maintained pain. Electrophysiological and pharmacological techniques will used to study catechol sensitization in nociceptors. Project IV examines the possible role of opiate analgesics in controlling a particular form of neuropathic pain (post-herpetic neuralgia). In a randomized, blinded, crossover study the efficacy of opiate analgesia will be compared to treatment with placebo, and the tricyclic antidepressant, amitriptyline. The "core" of this proposal will foster frequent interactions between clinicians and neuroscientists, and also provide for review by outside consultants. A particular strength of this project is that it will consider each level of the "pain axis" including the primary afferents, dorsal horn projection cells, thalamus, and finally the patient. This multidisciplinary yet highly focused attack on the problem of neuropathic pain will promote a synthesis of intellectual effort, and will potentially lead to new treatments.

Over the past year, five subjects have been screened using the established sensory test protocol (RPN: 77-06-27-01). Of the five subjects, three (i.e., subjects A,B,C) were found to be suitable for the capsaicin trial. As per approved protocol, they were given an epidural block. Only one foot was treated in a double blind procedure. Subjects A and B reported significant pain relief (25-50%) in the treated foot. Subject A also reported relief in the untreated foot. Subject C reported no pain relief, however, an improvement (i.e., normalization) of the sensory thresholds in the treated foot was found.

DESCRIPTION: (Adapted from the Investigator's Abstract) The long range objective of this research is to use neurophysiological and psychophysical techniques to develop a better understanding of pain perception. This strategy of correlative neurophysiological and psychophysical studies is a powerful technique to develop an understanding of neural encoding mechanisms. In our research we correlate the response of primary nociceptive afferents, obtained from single fiber recordings in the anesthetized monkey, with the response of human subjects, based on ratings of subjective magnitude. With this approach we have been able to make major inroads regarding the understanding of the peripheral as well as central neural mechanisms of pain and hyperalgesia. These studies provide a foundation to purse research on patients in order to understand and treat neuropathic pain. This proposal builds on prior work by continuing investigations into the role of nociceptors in normal pain sensation and by continuing neurophysiological and psychophysical studies of the mechanisms of hyperalgesia at the site of injury (primary hyperalgesia) and of hyperalgesia in the uninjured skin surrounding an injury (secondary hyperalgesia). These studies of primary and secondary hyperalgesia form the basis for investigations of hyperalgesia in neuropathic pain, a common and debilitating form of chronic pain. Numerous questions will be probed to address such issues as: (1) how does the branching structure of nociceptors affect signal processing? (2) What is the basis of fatigue in nociceptors? (3) Capsaicin is a potent drug in causing pain and hyperalgesia but also has therapeutic potential. Which classes of nociceptors signal the pain from capsaicin, and which classes are vulnerable to the toxic effects of capsaicin? (4) Two models of secondary hyperalgesia will be tested to gather information about the likely central nervous system mechanisms of this pathological feature of pain. (5) Finally these studies of hyperalgesia in normal volunteers will be directly applied to test highly focused hypotheses regarding the mechanisms and possible treatments of neuropathic pain in patients. This hypothesis driven research interrelates basic and clinical research in a mater that has excellent potential for promoting the understanding and treatment of pain.

[unreadable] DESCRIPTION (provided by applicant): Previous studies of neuropathic pain caused by nerve injury have focused on the abnormal properties of the axotomized primary sensory neuron. A proportion of such neurons develop ectopic discharge that can originate at the site of the nerve injury or more proximally in the dorsal root ganglion. Surprisingly, myelinated but not unmyelinated injured afferents exhibit ectopic discharges following a spinal nerve lesion. This has led to the speculation that myelinated fibers acquire the capacity to sensitize central neurons. An alternative mechanism for neuropathic pain comes from studies in our laboratory and others in which ectopic discharges have been found in intact unmyelinated nociceptors that commingle with axotomized axons. This spontaneous activity in unmyelinated afferents may initiate/maintain sensitization of central neurons. Indeed, a number of lines of evidence from preclinical and clinical studies point to a role of uninjured cutaneous nociceptors in neuropathic pain. We propose to address three fundamental questions regarding the properties of these intact, hyperexcitable sensory neurons. First, what kinds of neurons are they? This is important, because some types, like mechanically-insensitive afferents (MIAs) or C-fibers from muscle are believed to have a particularly important role in initiating/maintaining central sensitization. Second, is the transduction mechanism normal in nociceptive afferents or has it become sensitized? Hyperalgesia and allodynia may be due, at least in part, to an enhanced response of primary afferents to natural stimuli. Third, how enduring are these changes in primary afferent neurons? This is important because chronic neuropathic pain could have different mechanisms than acute neuropathic pain. To address these questions, we will perform blinded electrophysiological experiments in a primate model of neuropathic pain. These studies will provide a biological rationale for the development of peripheral treatments for neuropathic pain. [unreadable] [unreadable] [unreadable]