Thomas J. Morrow, PhD - US grants

Some neurons in the CNS at cortical, diencephalic and subdiencephalic levels have been shown to exhibit changes in spontaneous discharge with corresponding changes in the animal's state of arousal. We propose to identify and study, in the awake, behaving monkey, thalamic somatosensory neurons showing similar changes in spontaneous activity, as well as, those showing changes in responsiveness to somatic stimuli related to the level of arousal. It is our hypothesis that at least two distinct classes of neurons will be found in the ventral posterior portion of the thalamus. One group, the state independent somatosensory (AIS) neurons, will have discrete, usually contralateral receptive fields and show little or no variation in stimulus responsiveness or receptive field size as the monkey's state of arousal ranges from sleep to drowsy to awake and alert. The other class, called state dependent somatosensory (ADS) neurons, will show changes in unit excitability as a function of the animal's level of arousal. These changes may include increases in spontaneous discharge with increased arousal, or altered responsiveness to a somatic stimulus, or both. The responses of single neurons to somatic stimuli will be recorded in the ventrolateral and posterior thalamus of African green monkeys during three behaviorally and electroencephalographically defined states of arousal. Several measures of neuronal responsiveness will be made by an on-line computer and significant changes in unit activity that are associated with changes in arousal will be determined. Focal electrical stimulation of lemniscal and/or spinothalamic input at the midbrain level will be employed to determine the extent to which arousal related changes in thalamic somatosensory excitability are mediated indirectly by modulation at subthalamic levels or by acting directly at the thalamic level. In addition, functional lesions of the somatosensory thalamus and electrical stimulation of the thalamic reticular nucleus will be used to determine whether these structures are responsible for the production of arousal-related modulation by direct action at the thalamic level.

Partial deafferentation due to incomplete damage to a peripheral somatic nerve by traumatic injury or disease can often produce bizarre and intractable abnormalities in pain perception in humans and animals. These include spontaneous pain in the denervated area and hyperalgesia and allodynia in both the denervated as well as the adjacent innervated area. Our current understanding of the pathophysiology of these phenomena is incomplete. However, there is increasing evidence that altered central nervous system processing plays a key role in the development of these chronic pain conditions. We hypothesize that following complete or partial nerve injury, plastic changes occur, resulting in new patterns of activation for multiple CNS structures forming a forebrain network for pain processing. It is this central reorganization that we propose is responsible for the development and maintenance of chronic pain in peripheral neuropathy. In addition, we propose that the efficacy of conventional analgesic interventions may be dependant on their ability to modify these reorganized patterns of forebrain activation. We will use a three phase approach to characterize the dynamic reorganization within the forebrain network for pain processing. First, we will behaviorally characterize the development of chronic neuropathic pain (CNP) in a well defined animal model of peripheral mononeuropathy due to chronic constriction injury of the sciatic nerve in rat. Several analgesic interventions will be evaluated for their relative ability to reduce behaviors indicative of chronic pain. In phase two, using regional cerebral blood flow as a measure of neuronal activity, we will identify forebrain cerebral metabolic activation patterns (CMAPs) induced by noxious and innocuous stimuli in normal and sham operated rats. In addition we will assess how behaviorally effective analgesic treatments modify these CMAPs. In the final phase, we will investigate the functional reorganization within this forebrain network during the development of CNP and the modification of these forebrain activation patterns by behaviorally effective analgesic interventions. This research promises to identify forebrain activation patterns indicative of the development of CNS reorganization in chronic neuropathic pain. Increasing our understanding of the neural mechanisms of chronic pain in peripheral neuropathy, may help in the development of new approaches and therapies for the management and treatment of patients with this disorder.

[unreadable] DESCRIPTION (provided by applicant): Diabetic neuropathy affects approximately 30% of patients with diabetes mellitus with many patients experiencing severe and unremitting spontaneous pain. In addition diabetic patients frequently exhibit abnormal stimulus-evoked pains, including an increased responsiveness to noxious stimuli (hyperalgesia) as well as a hyper-responsiveness to normally innocuous stimuli (allodynia). Unfortunately, the mechanisms of chronic neuropathic pain (CNP) in diabetes are not clear. However, there is increasing evidence that altered central nervous system (CNS) processing plays a key role in the development of chronically painful conditions. Accordingly, we propose to identify CNS mechanisms of chronic neuropathic pain (CNP) in diabetes, by combining behavioral pain assessment with functional brain imaging in the streptozotocin (STZ) diabetic rat model. We hypothesize that a significant proportion of STZ-diabetic rats will develop behavioral indices of a chronic neuropathic pain state, including mechanical allodynia and thermal hyperalgesia. We propose that as a consequence of and/or in parallel to the development of a diabetic neuropathy, maladaptive alterations occur in the functional activation of multiple CNS structures involved in pain perception and/or pain modulation. We propose to identify pain-related increases in the baseline (unstimulated) and stimulus-evoked activation of specific cortical (SI, SII, CC and RS) and thalamic (VPL and AD) brain regions in diabetic rats that correlate with the development of CNP. Furthermore we hypothesize that these pain-specific increases in activation within the above cortical and thalamic structures are not merely a reflection of abnormal input from peripheral and spinal levels, but that these supraspinal structures actively participate to produce and/or maintain the neuropathic pain state. Finally, we propose that CNP in diabetes mellitus is due not only to activation of specific thalamic and cortical structures involved in processing nociceptive input, but is also due to the concurrent deactivation of the brainstem periaqueductal gray (PAG), a brain region involved in endogenous antinociception. This research promises to identify critical supraspinal mechanisms of chronic neuropathic pain in diabetes mellitus. [unreadable] [unreadable]