Highlights
- •Malocclusion induces widespread somatic pain hypersensitivity, a typical characteristic of fibromyalgia syndrome.
- •Cholecystokinin -dependent descending facilitation contributes to the development of temporomandibular disorders and fibromyalgia syndrome comorbidity.
- •IL-18 in the spinal cord is important for the development of somatic pain hypersensitivity.
- •Cholecystokinin /IL-18-mediated neuronal and glial cascades are involved in the somatic pain hypersensitivity.
Abstract
Recent studies have shown that the incidence of chronic primary pain including temporomandibular
disorders (TMD) and fibromyalgia syndrome (FMS) often exhibit comorbidities. We recently
reported that central sensitization and descending facilitation system contributed
to the development of somatic pain hypersensitivity induced by orofacial inflammation
combined with stress. The purpose of this study was to explore whether TMD caused
by unilateral anterior crossbite (UAC) can induce somatic pain hypersensitivity, and
whether the cholecystokinin (CCK) receptor-mediated descending facilitation system
promotes hypersensitivity through neuron-glia cell signaling cascade. UAC evoked thermal
and mechanical pain hypersensitivity of the hind paws from day 5 to 70 that peaked
at week 4 post UAC. The expression levels of CCK1 receptors, interleukin-18 (IL-18)
and IL-18 receptors (IL-18R) were significantly up-regulated in the L4 to L5 spinal
dorsal horn at 4 weeks post UAC. Intrathecal injection of CCK1 and IL-18 receptor
antagonists blocked somatic pain hypersensitivity. IL-18 mainly co-localized with
microglia, while IL-18R mainly co-localized with astrocytes and to a lesser extent
with neurons. These findings indicate that the signaling transduction between neurons
and glia at the spinal cord level contributes to the descending pain facilitation
through CCK1 receptors during the development of the comorbidity of TMD and FMS.
Perspective
CCK1 receptor-dependent descending facilitation may mediate central mechanisms underlying
the development of widespread somatic pain via a reciprocal neuron-glial signaling
cascade, providing novel therapeutic targets for the clinical treatment of TMD and
FMS comorbidities.
Key words
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Article info
Publication history
Published online: June 09, 2022
Accepted:
May 25,
2022
Received in revised form:
May 5,
2022
Received:
December 21,
2021
Footnotes
This work was supported by the National Natural Science Foundation of China (81971049, 81671097), the Social Development Program of Shaanxi Province, China (2020SF-018) to DYC, and the National Institutes of Health, USA (R01 DE029074) to RJT.
The authors state they have no conflict of interest.
Identification
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© 2022 by United States Association for the Study of Pain, Inc.
