Although 10-15% of the United States population suffers from chronic widespread musculoskeletal pain (CWP), the etiology of these conditions is virtually unknown. CWP syndromes, such as fibromyalgia, are disabling and difficult to treat. To more fully characterize the mechanisms that initiate and drive CWP, we developed an animal model with widespread mechanical hyperalgesia that mimics CWP. Repeated intramuscular injections of acid into one gastrocnemius muscle is a unique model since there is bilateral mechanical hyperalgesia without peripheral tissue damage, and the contralateral hyperalgesia is not maintained by peripheral afferent activity. In parallel to the bilateral hyperalgesia, 1) there are bilateral increases in the spinal cord for the phosphorylation of the transcription factor, CREB (cAMP responsive element binding protein); 24 h following induction of long-lasting muscle pain with acid, and 2) ipsilateral dorsal horn neurons show an expansion of their receptive fields to include the contralateral limb. We posit that these bilateral events distant from the site of insult reflect increased facilitatory influences from the brainstem. In support, descending facilitator/ pathways from the rostroventral medial medulla (RVM) mediate or maintain secondary hyperalgesia produced by intra-articular carrageenan, and the hyperalgesia associated with neuropathic pain and visceral inflammation. The spinal projections from these nuclei are bilateral, and receptive fields of these medullary neurons are widespread and include the contralateral hind limb.
The Specific Aims will determine if local anesthetic or receptor blockade of the RVM during the first or second injection of acidic saline prevents, or after induction of hyperalgesia reverses the bilateral mechanical hyperalgesia and spinal increases in p-CREB produced by repeated intramuscular acid injection, a model of non-inflammatory widespread muscle pain. We will also determine if there is an increased release of glutamate in the RVM in response to the second injection of acidic saline. These studies will be the first to examine the role of Q descending facilitation following muscle insult and will further determine if descending facilitatory influences drive the spinal cord changes. We expert that the bilateral hyperalgesia and bilateral spinal increases in p-CREB that occur after muscle insult will be prevented by supraspinal blockade of input at the time of insult, and reversed by supraspinal blockade after development of hyperalgesia. These studies will also be the first to determine the release pattern for glutamate in the RVM in response to tissue injury. We expect an increase in glutamate in response to the second injection of acidic saline that parallels the hyperalgesia. If so, these data would suggest that supraspinal influences in the RVM utilizing glutamate are critical for the generation and the maintenance of bilateral hyperalgesia and spinal cord changes. A better understanding of the pathobiological mechanisms underlying musculoskeletal pain conditions may lead to the development of novel therapeutic approaches for its treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052316-02
Application #
7125456
Study Section
Special Emphasis Panel (ZRG1-CFS (01))
Program Officer
Serrate-Sztein, Susana
Project Start
2005-09-20
Project End
2010-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$316,874
Indirect Cost
Name
University of Iowa
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Gregory, Nicholas S; Brito, Renan G; Fusaro, Maria Cláudia G Oliveira et al. (2016) ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia. Mol Neurobiol 53:1020-30
Corrêa, Juliana Barbosa; Costa, Leonardo Oliveira Pena; de Oliveira, Naiane Teixeira Bastos et al. (2015) Central sensitization and changes in conditioned pain modulation in people with chronic nonspecific low back pain: a case-control study. Exp Brain Res 233:2391-9
Sluka, Kathleen A; Gregory, Nicholas S (2015) The dichotomized role for acid sensing ion channels in musculoskeletal pain and inflammation. Neuropharmacology 94:58-63
da Silva, Morgana D; Bobinski, Franciane; Sato, Karina L et al. (2015) IL-10 cytokine released from M2 macrophages is crucial for analgesic and anti-inflammatory effects of acupuncture in a model of inflammatory muscle pain. Mol Neurobiol 51:19-31
Gregory, Nicholas S; Sluka, Kathleen A (2014) Anatomical and physiological factors contributing to chronic muscle pain. Curr Top Behav Neurosci 20:327-48
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Sanada, Luciana Sayuri; Sato, Karina Laurenti; Machado, Nathalia Leilane Berto et al. (2014) Cortex glial cells activation, associated with lowered mechanical thresholds and motor dysfunction, persists into adulthood after neonatal pain. Int J Dev Neurosci 35:55-63
Sluka, Kathleen A (2013) Peripheral and central mechanisms of chronic musculoskeletal pain. Pain Manag 3:103-107
Sluka, Kathleen A; Bjordal, Jan M; Marchand, Serge et al. (2013) Author response. Phys Ther 93:1427-8

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