Whiplash and its associated syndromes continue to be ranked among the most common and debilitating nonfatal injuries. Painful injury of the cervical facet capsule occurs because altered neck motions during whiplash results in mechanical injury to the sensory afferents in the facet joint's capsule. However, due to a lack of relevant in vivo systems modeling biomechanical neck injuries, little is known about the mechanisms of neck pain resulting from whiplash. We recently developed a rat model that simulates the biomechanical loading conditions of the cervical facet joint during whiplash. It is the long-term objective of this application to use that model to define the effects of local joint biomechanics on capsule afferent responses, spinal mechanisms of nociception, and the resulting behavioral sensitivity. We hypothesize that: (1) whiplash-like loading of the facet joint produces persistent pain via altered neurochemical function of the peptidergic and non-peptidergic C- fibers in the facet capsule, (2) the biochemical responses of those capsule afferents have permanent effects on neuropeptides, neurotrophins and immune responses (i.e. glial activation, pro-inflammatory cytokines) in the spinal cord, and (3) whiplash loading produces inflammation in the facet joint that also exacerbates spinal modifications and pain symptoms. We have pilot data demonstrating that a transient whiplash-like loading scenario produces both persistent behavioral sensitivity in the neck and sustained spinal modifications in our rat model. In this proposal we will define the temporal relationship between joint biomechanics, neuropeptide and neurotrophin regulation and immune responses in the dorsal root ganglion and spinal cord, and behavioral sensitivity.
In Aim 1 we will define these responses for painful whiplash loading to the C6/C7 facet joint.
In Aim 2 we use saporin conjugates in separate studies to selectively eliminate NK1 receptor-bearing and IB4-positive neurons in the facet joint and define their relative contributions to pain and nociception by comparison to outcomes in Aim 1.
In Aim 3 we will impose a non-painful joint loading scenario and also ablate NK1 receptor- bearing neurons in the spinal cord to identify which spinal responses are specific for painful joint biomechanics. Lastly, in Aim 4 we will test if inhibiting the inflammatory cascade in the facet joint can prevent or attenuate sensitivity and/or modulate associated spinal responses. By accomplishing the specific aims of this research, we will directly link the initial mechanical conditions of the facet joint to pain pathways in the central nervous system. In turn, we will define the etiology for persistent pain from neck loading, leading to the development of potential treatments to treat whiplash-related neck pain.

Public Health Relevance

Whiplash is a public health burden, with staggering annual societal and financial consequences. This research proposal will define mechanisms of whiplash injury that produce persistent pain and will identify how sensory fibers in the facet joint contribute to the onset and maintenance of such symptoms. Physiologic correlates of these injuries and symptoms are also characterized to guide future development of preventions and treatments for neck pain from this common class of injuries for vehicle occupants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056288-02
Application #
7769895
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Panagis, James S
Project Start
2009-04-01
Project End
2014-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$298,416
Indirect Cost
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Singh, Sagar; Kartha, Sonia; Bulka, Ben A et al. (2018) Physiologic facet capsule stretch can induce pain & upregulate matrix metalloproteinase-3 in the dorsal root ganglia when preceded by a physiological mechanical or nonpainful chemical exposure. Clin Biomech (Bristol, Avon) :
Weisshaar, Christine L; Kras, Jeffrey V; Pall, Parul S et al. (2017) Ablation of IB4 non-peptidergic afferents in the rat facet joint prevents injury-induced pain and thalamic hyperexcitability via supraspinal glutamate transporters. Neurosci Lett 655:82-89
Ita, Meagan E; Crosby, Nathan D; Bulka, Ben A et al. (2017) Painful Cervical Facet Joint Injury Is Accompanied by Changes in the Number of Excitatory and Inhibitory Synapses in the Superficial Dorsal Horn That Differentially Relate to Local Tissue Injury Severity. Spine (Phila Pa 1976) 42:E695-E701
Crosby, Nathan D; Winkelstein, Beth A (2016) Spinal Astrocytic Thrombospondin-4 Induced by Excitatory Neuronal Signaling Mediates Pain After Facet Capsule Injury. Ann Biomed Eng 44:3215-3224
Kras, J V; Kartha, S; Winkelstein, B A (2015) Intra-articular nerve growth factor regulates development, but not maintenance, of injury-induced facet joint pain & spinal neuronal hypersensitivity. Osteoarthritis Cartilage 23:1999-2008
Crosby, Nathan D; Zaucke, Frank; Kras, Jeffrey V et al. (2015) Thrombospondin-4 and excitatory synaptogenesis promote spinal sensitization after painful mechanical joint injury. Exp Neurol 264:111-20
Kras, Jeffrey V; Weisshaar, Christine L; Pall, Parul S et al. (2015) Pain from intra-articular NGF or joint injury in the rat requires contributions from peptidergic joint afferents. Neurosci Lett 604:193-8
Weisshaar, Christine L; Winkelstein, Beth A (2014) Ablating spinal NK1-bearing neurons eliminates the development of pain and reduces spinal neuronal hyperexcitability and inflammation from mechanical joint injury in the rat. J Pain 15:378-86
Kras, Jeffrey V; Dong, Ling; Winkelstein, Beth A (2014) Increased interleukin-1? and prostaglandin E2 expression in the spinal cord at 1 day after painful facet joint injury: evidence of early spinal inflammation. Spine (Phila Pa 1976) 39:207-12
Crosby, Nathan D; Gilliland, Taylor M; Winkelstein, Beth A (2014) Early afferent activity from the facet joint after painful trauma to its capsule potentiates neuronal excitability and glutamate signaling in the spinal cord. Pain 155:1878-87

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