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.

Project Start
1998-08-01
Project End
1999-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Casey, Kenneth L; Geisser, Michael; Lorenz, J├╝rgen et al. (2012) Psychophysical and cerebral responses to heat stimulation in patients with central pain, painless central sensory loss, and in healthy persons. Pain 153:331-41
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Hong, Shuangsong; Morrow, Thomas J; Paulson, Pamela E et al. (2004) Early painful diabetic neuropathy is associated with differential changes in tetrodotoxin-sensitive and -resistant sodium channels in dorsal root ganglion neurons in the rat. J Biol Chem 279:29341-50
Casey, Kenneth L; Lorenz, Jurgen; Minoshima, Satoshi (2003) Insights into the pathophysiology of neuropathic pain through functional brain imaging. Exp Neurol 184 Suppl 1:S80-8
Lorenz, J; Minoshima, S; Casey, K L (2003) Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation. Brain 126:1079-91
Lorenz, Jurgen; Cross, Donna J; Minoshima, Satoshi et al. (2002) A unique representation of heat allodynia in the human brain. Neuron 35:383-93
Paulson, Pamela E; Casey, Kenneth L; Morrow, Thomas J (2002) Long-term changes in behavior and regional cerebral blood flow associated with painful peripheral mononeuropathy in the rat. Pain 95:31-40
Casey, K L; Morrow, T J; Lorenz, J et al. (2001) Temporal and spatial dynamics of human forebrain activity during heat pain: analysis by positron emission tomography. J Neurophysiol 85:951-9
Paulson, P E; Morrow, T J; Casey, K L (2000) Bilateral behavioral and regional cerebral blood flow changes during painful peripheral mononeuropathy in the rat. Pain 84:233-45
Casey, K L; Svensson, P; Morrow, T J et al. (2000) Selective opiate modulation of nociceptive processing in the human brain. J Neurophysiol 84:525-33

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