Decades of studies have provided ample evidence that glial neuroimmune activation contributes in the development of neuropathic pain. However, knowledge regarding the role of neural-glial interactions in the pathophysiology of neuropathic pain is currently lacking. In preclinical studies, calcitonin gene related peptide (CGRP), a peptide neurotransmitter, has been shown to be involved in peripheral nerve injuryinduced tactile hypersensitivity, a behavioral sign of neuropathic pain. Previously, we have also demonstrated a critical role of central nervous system (CNS) microglial CD40 in the maintenance of mechanical hypersensitivity post-peripheral nerve injury. In the current study, the possible interactions between microglial CD40 signaling and primary afferent neuron-released CGRP in regards to they affect glial cells in the spinal cord will be investigated. We hypothesize that following peripheral nerve injury, spinal cord CD40 mediates the release of CGRP from primary afferent nociceptors and this CGRP release promotes persistent pain behavior, particularly during the maintenance phase, through the induction of proinflammatory chemokine production by glia. This central hypothesis will be tested via both in vivo and in vitro studies. An established rodent neuropathic pain model, spinal nerve L5 transection (L5Tx), will be used for the in vivo studies. Dorsal root ganglia (DRG) neuron-microglia co-cultures and mixed glial cultures will be generated for the in vitro studies. The central hypothesis will be tested through 4 specific aims: 1) Examine lumbar spinal cord chemokine production following L5Tx in CD40 KO mice vs. WT mice and the role of selected chemokines in the development of behavioral hypersensitivity;2) Determine whether CGRP is involved in L5Tx-induced chemokine production and behavioral hypersensitivity;3) Evaluate the role of microglial CD40 in CGRP release by primary afferent neurons;and 4) Assess glial production of selected proinflammatory chemokines and upstream signaling pathways (mainly mitogen-activated protein kinase pathways) following CGRP stimulation in mixed glial cultures. The long-term goal of our study is to further understand the pathophysiology of nerve injury-induced neuropathic pain in order to uncover novel targets for new drug development leading to more efficacious treatments of neuropathic pain.

Public Health Relevance

Neuropathic pain, defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system, is one of the most devastating kinds of chronic pain and is still largely treated sub-optimally. Delineating the mechanisms leading to neuropathic pain is of crucial importance and will accelerate the design of new, more effective treatments.

Agency
National Institute of Health (NIH)
Type
Exploratory Grants (P20)
Project #
5P20GM103643-03
Application #
8689115
Study Section
Special Emphasis Panel (ZRR1)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of New England
Department
Type
DUNS #
City
Biddeford
State
ME
Country
United States
Zip Code
04005
McLane, Virginia D; Cao, Ling; Willis, Colin L (2014) Morphine increases hippocampal viral load and suppresses frontal lobe CCL5 expression in the LP-BM5 AIDS model. J Neuroimmunol 269:44-51
Camire, Ryan B; Beaulac, Holly J; Brule, Stephanie A et al. (2014) Biphasic modulation of paracellular claudin-5 expression in mouse brain endothelial cells is mediated through the phosphoinositide-3-kinase/AKT pathway. J Pharmacol Exp Ther 351:654-62
Li, Yingxue; St Louis, Lindsay; Knapp, Brian I et al. (2014) Can amphipathic helices influence the CNS antinociceptive activity of glycopeptides related to ?-endorphin? J Med Chem 57:2237-46
Burman, Michael A; Simmons, Cassandra A; Hughes, Miles et al. (2014) Developing and validating trace fear conditioning protocols in C57BL/6 mice. J Neurosci Methods 222:111-7
Meng, Ian D; Kurose, Masayuki (2013) The role of corneal afferent neurons in regulating tears under normal and dry eye conditions. Exp Eye Res 117:79-87
Wang, Yong; Lin, Lu; Lai, Helen et al. (2013) Transcription factor Sox11 is essential for both embryonic and adult neurogenesis. Dev Dyn 242:638-53