Pain is the most common motive leading people to seek health care. When it becomes chronic, pain can produce several long term effects such as depression, loss of sleep, depressed immune function, decreased mobility, and other long-term deleterious consequences, several of which suggest the involvement of cortical areas implicated in higher cognitive functions. Although animal models advanced over the last 15 years have revolutionized our understanding of chronic pain mechanisms, the knowledge garnered in these models has concentrated primarily on mechanisms involving afferent inputs, spinal cord processes, and descending modulation. Little is known about supraspinal mechanisms, even less so about the interaction of pain and cortical processes. Recent human brain imaging studies in chronic back pain patients indicate medial prefrontal cortical hyperactivity, even in absence of nociceptive peripheral inputs. Other studies show impairment of decision making tasks in patients suffering of chronic pain and animal models show that blocking neuronal activity in the medial prefrontal cortex reversibly decreases neuropathic pain. Animal studies on inflammatory pain show functional consequences on glutamatergic synaptic transmission in the prefrontal cortex. All these observations suggest that functional and morphological changes may be present in the prefrontal cortex of animals with neuropathic pain. We will investigate this hypothesis in SNI rats, a highly reproducible model of neuropathic pain. Patch clamp recordings and morphological analysis of biocytin filled neurons will be performed to compare the functional and morphological properties of pyramidal neurons of the medial prefrontal cortex (mPFC) of SNI and sham-operated animals. We will compare the number and length of the dendrites and the dendritic spine density in SNI and sham-operated animals. Immunohistochemical analysis will be performed to investigate the expression of molecular markers of neuronal reorganization. Intrinsic electrophysiological properties as well as the pharmacological properties of glutamatergic synaptic transmission will also be investigated. Nucleated patch recordings and fast solution exchange will be used to perform a detailed study of the functional properties of the glutamate receptors expressed in mPFC pyramidal neurons of control and SNI rats. Our preliminary data show that, compared to sham-operated counterparts, mPFC neurons from SNI rats expressed higher levels of c-Fos, have larger dendritic trees, increased dendritic spine density and different molecular composition of glutamate receptors. Interestingly, several of these changes are correlated with the pain threshold in the injured paw. These observations support our hypothesis that neuropathic pain induces functional reorganization of the mPFC. Successful completion of our experiments could represent a leap forward in the study of the cellular mechanisms of neuropathic pain and open new fields of investigation.

Public Health Relevance

Chronic pain can cause long term consequences such as depression, loss of sleep, and changes in eating patterns, all of which imply the involvement of cortical areas implicated in higher cognitive functions;this suggests that pain can affect the function and, possibly, the anatomical organization of these brain areas, although little is known about the effect of chronic pain on the brain. We will study neuropathic pain-induced functional and morphological reorganization of the prefrontal cortex;such experiments will advance the knowledge of the cellular mechanisms of neuropathic pain and cortical plasticity, and may lead to novel therapeutic strategies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Chen, Daofen
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Northwestern University at Chicago
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Kelly, Crystle J; Martina, Marco (2018) Circuit-selective properties of glutamatergic inputs to the rat prelimbic cortex and their alterations in neuropathic pain. Brain Struct Funct 223:2627-2639
Pollema-Mays, Sarah L; Centeno, Maria Virginia; Chang, Zheng et al. (2018) Reduced ?FosB expression in the rat nucleus accumbens has causal role in the neuropathic pain phenotype. Neurosci Lett :
Radzicki, Daniel; Pollema-Mays, Sarah L; Sanz-Clemente, Antonio et al. (2017) Loss of M1 Receptor Dependent Cholinergic Excitation Contributes to mPFC Deactivation in Neuropathic Pain. J Neurosci 37:2292-2304
Kelly, Crystle J; Huang, Mei; Meltzer, Herbert et al. (2016) Reduced Glutamatergic Currents and Dendritic Branching of Layer 5 Pyramidal Cells Contribute to Medial Prefrontal Cortex Deactivation in a Rat Model of Neuropathic Pain. Front Cell Neurosci 10:133
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Chang, Pei-Ching; Pollema-Mays, Sarah Lynn; Centeno, Maria Virginia et al. (2014) Role of nucleus accumbens in neuropathic pain: linked multi-scale evidence in the rat transitioning to neuropathic pain. Pain 155:1128-39
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Pollema-Mays, Sarah L; Centeno, Maria Virginia; Ashford, Crystle J et al. (2013) Expression of background potassium channels in rat DRG is cell-specific and down-regulated in a neuropathic pain model. Mol Cell Neurosci 57:1-9
Radzicki, Daniel; Yau, Hau-Jie; Pollema-Mays, Sarah L et al. (2013) Temperature-sensitive Cav1.2 calcium channels support intrinsic firing of pyramidal neurons and provide a target for the treatment of febrile seizures. J Neurosci 33:9920-31

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