Sensory and sympathetic nerve fibers undergo sprouting and neuroma formation in the painful arthritic joint of geriatric mice
AffiliationDepartment of Pharmacology, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA
Unidad Académica Multidisciplinaria Reynosa Aztlán, Universidad Autónoma de Tamaulipas, Calle 16 y Lago de Reynosa, Reynosa, 88740, México
Arizona Cancer Center, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA
Research Service, VA Medical Center, One Veterans Drive, Minneapolis, MN 55417, USA
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CitationJimenez-Andrade and Mantyh Arthritis Research & Therapy 2012, 14:R101 http://arthritis-research.com/content/14/3/R101
JournalArthritis Research & Therapy
Rights© 2012 Mantyh et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).
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AbstractINTRODUCTION:Although the prevalence of arthritis dramatically increases with age, the great majority of preclinical studies concerning the mechanisms that drive arthritic joint pain have been performed in young animals. One mechanism hypothesized to contribute to arthritic pain is ectopic nerve sprouting
however, neuroplasticity is generally thought to be greater in young versus old nerves. Here we explore whether sensory and sympathetic nerve fibers can undergo a significant ectopic nerve remodeling in the painful arthritic knee joint of geriatric mice.METHODS:Vehicle (saline) or complete Freund's adjuvant (CFA) was injected into the knee joint of 27- to 29-month-old female mice. Pain behaviors, macrophage infiltration, neovascularization, and the sprouting of sensory and sympathetic nerve fibers were then assessed 28 days later, when significant knee-joint pain was present. Knee joints were processed for immunohistochemistry by using antibodies raised against CD68 (monocytes/macrophages), PECAM (endothelial cells), calcitonin gene-related peptide (CGRP
sensory nerve fibers), neurofilament 200 kDa (NF200
sensory nerve fibers), tyrosine hydroxylase (TH
sympathetic nerve fibers), and growth-associated protein 43 (GAP43
nerve fibers undergoing sprouting).RESULTS:At 4 weeks after initial injection, CFA-injected mice displayed robust pain-related behaviors (which included flinching, guarding, impaired limb use, and reduced weight bearing), whereas animals injected with vehicle alone displayed no significant pain-related behaviors. Similarly, in the CFA-injected knee joint, but not in the vehicle-injected knee joint, a remarkable increase was noted in the number of CD68+ macrophages, density of PECAM+ blood vessels, and density and formation of neuroma-like structures by CGRP+, NF200+, and TH+ nerve fibers in the synovium and periosteum.CONCLUSIONS:Sensory and sympathetic nerve fibers that innervate the aged knee joint clearly maintain the capacity for robust nerve sprouting and formation of neuroma-like structures after inflammation/injury. Understanding the factors that drive this neuroplasticity, whether this pathologic reorganization of nerve fibers contributes to chronic joint pain, and how the phenotype of sensory and sympathetic nerves changes with age may provide pharmacologic insight and targets for better controlling aging-related joint pain.
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Except where otherwise noted, this item's license is described as © 2012 Mantyh et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).