Mechanisms of Spontaneous Neuropathic Pain

Project: Research project

Grant Details


DESCRIPTION (provided by applicant): Current options for treatment of neuropathic pain remain unsatisfactory in part because of an inadequate understanding of mechanisms of this abnormal pain condition. Experimental neuropathic pain is characterized by the presence of enhanced behavioral responses to noxious or normally non-noxious sensory stimuli (i.e., allodynia). The presence of such enhanced responses is generally accepted as a translational and validating feature of the experimental pain condition and modulation of enhanced sensory thresholds is commonly used to explore mechanisms relevant to potential therapy. Studies in humans, however, have shown that changes in evoked thresholds (i.e., allodynia) frequently do not correlate with reductions in pain scores. Rather, it is the spontaneous aspects of the human pain experience that lead patients to seek treatment for their neuropathic pain. Thus, a critical shortcoming with regard to experimental evaluation of neuropathic pain is the reliability and predictive value of studies involving modulation of evoked reflexive responses to sensory stimuli and subsequent interpretation of mechanism. Experimental measurement of spontaneous pain following peripheral nerve injury has been difficult. Whether mechanisms which mediate spontaneous neuropathic pain may be distinct from those mediating enhanced evoked responses following injury is not known. We have recently demonstrated that microinjection of lidocaine into an area of the brain that mediates descending modulation of pain (i.e., the rostral ventromedial medulla or RVM) produces preference in a conditioned place pairing (CPP) paradigm in nerve injured, but not in sham-operated, rats. Additionally, we have shown that spinal administration of drugs that are known to produce relief of neuropathic pain clinically (i.e., clonidine, -conotoxin), will produce place preference only in nerve injured rats. The demonstration of place preference in nerve-injured, but not sham-operated, rats following administration of drugs which are known to activate reward pathways and in areas of the nervous system (i.e., brainstem and spinal cord) which are not a part of the reward pathway suggests the presence and modulation of spontaneous neuropathic pain. While nerve injury-induced evoked hypersensitivity (i.e., allodynia/hyperalgesia) and spontaneous neuropathic pain are likely to involve some common mechanisms, we hypothesize that evoked and spontaneous neuropathic pain can also be distinguished mechanistically (as shown by our preliminary data). The experiments proposed in this application will explore the mechanisms mediating spontaneous neuropathic pain by determining the role of (a) specific pronociceptive transmitters from primary afferent fibers innervating the spinal cord or brainstem nuclei (Aim 1), (b) subtypes of sodium channels which important in ectopic discharge (Aim 2) and (c) mediators of the descending pain modulatory pathway from the RVM and at the level of the spinal cord. At present, almost no information is known about mechanisms of human spontaneous pain beyond the limited information gained from the activity of currently employed medications that have complex pharmacology. This proposal seeks new insights into potential mechanisms of one of the most important symptoms of the human neuropathic state. Discoveries related to specific mechanisms of spontaneous pain will increase opportunities for clinical translation. PUBLIC HEALTH RELEVANCE: Injuries to nerves can result in a chronic debilitating pain condition termed neuropathic pain that affects many millions of Americans. Medical treatment for this pain condition is inadequate and the impact on society is enormous whether measured in terms of human suffering or from an economic perspective involving lost productivity and treatment. Increased understanding of mechanisms of this pain condition can lead to new and effective therapy.
Effective start/end date5/1/104/30/15


  • National Institutes of Health: $323,226.00
  • National Institutes of Health: $319,900.00
  • National Institutes of Health: $311,869.00
  • National Institutes of Health: $323,272.00
  • National Institutes of Health: $329,734.00


  • Medicine(all)
  • Neuroscience(all)


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