The Prostaglandin E2 Receptor, EP2, Is Upregulated in the Dorsal Root Ganglion After Painful Cervical Facet Joint Injury in the Rat

Abstract

Study Design This study implemented immunohistochemistry to assay prostaglandin E2 (PGE2) receptor EP2 expression in the dorsal root ganglion (DRG) of rats after painful cervical facet joint injury. Objective The objective of this study was to identify if inflammatory cascades are induced in association with cervical facet joint distraction-induced pain by investigating the time course of EP2 expression in the DRG. Summary of Background Data The cervical facet joint is a common source of neck pain and non-physiological stretch of the facet capsular ligament can initiate pain from the facet joint via mechanical injury. PGE2 levels are elevated in painful inflamed and arthritic joints, and PGE2 sensitizes joint afferents to mechanical stimulation. Although in vitro studies suggest the EP2 receptor subtype contributes to painful joint disease the EP2 response has not been investigated for any association with painful mechanical joint injury. Methods Separate groups of male Holtzman rats underwent either a painful cervical facet joint distraction injury or sham procedure. Bilateral forepaw mechanical allodynia was assessed, and immunohistochemical techniques were used to quantify EP2 expression in the DRG at days 1 and 7. Results Facet joint distraction induced mechanical allodynia that was significant (p<0.024) at all time points. Painful joint injury also significantly elevated total EP2 expression in the DRG at day 1 (p=0.009), which was maintained also at day 7 (p<0.001). Neuronal expression of EP2 in the DRG was only increased over sham levels at day 1 (p=0.013). Conclusions Painful cervical facet joint distraction induces an immediate and sustained increase of EP2 expression in the DRG, implicating peripheral inflammation in the initiation and maintenance of facet joint pain. The transient increase in neuronal EP2 suggests, as in other painful joint conditions, that after joint injury non-neuronal cells may migrate to the DRG, some of which likely express EP2.

An Anatomical and Immunohistochemical Characterization of Afferents Innervating the C6–C7 Facet Joint After Painful Joint Loading in the Rat

“…Three days after the CTb injection, a subset of rats underwent either a painful cervical facet joint distraction injury (n=4) or sham procedure (n=5), as described previously [12,16,36]. Under inhalation anesthesia, the surgical staples and suture were removed, and the C6/C7 facet joints were re-exposed.…”

Increased Interleukin-1α and Prostaglandin E2 Expression in the Spinal Cord at 1 Day After Painful Facet Joint Injury

“…The PGE 2 receptors, EP1, EP2, and EP4, have all been shown to contribute to PGE 2 -induced hyperalgesia [45,46]. We previously reported an increase in expression of the PGE 2 receptor EP2 in the DRG after this same joint injury [6]. As such, it is likely that increased EP2 expression in the DRG corresponds to increased EP2 in the presynaptic terminals of the spinal cord; however, spinal expression of any of the PGE 2 receptors was not quantified in our study but would help to identify those receptors through which PGE 2 acts and would more completely define its mechanism of action related to joint pain.…”

“…The facet joint has been identified as one of the most common sources of neck pain and remains a likely candidate for injury due to its mechanical vulnerability and its innervation by nerve fibers, and nociceptors in particular, in its capsular ligament [3–5]. Painful facet joint injury and inflammation have been reported to upregulate inflammatory cytokines and the prostaglandin E 2 (PGE 2 ) receptor, EP2, in primary afferent neurons [6–8], implicating inflammation as a key component of pain from the facet joint. Moreover, loading-induced joint pain can be alleviated through the intra-articular injection of ketorolac, a non-steroidal anti-inflammatory drug [9], supporting the assertion that inflammation contributes to facet joint pain.…”

A Nociceptive Role for Integrin Signaling in Pain After Mechanical Injury to the Spinal Facet Capsular Ligament

“…Inflammatory mediators acting on their cell membrane receptors trigger intracellular mechanisms can regulate both focal adhesions and the cytoskeleton, initiating second messenger cascades, such as the ERK and the PKC pathways, that lead to pain. 3,12,17,20,32,35,46 The increased expression of integrin subunits a few days after a painful facet capsule injury (Figure 4) points to possible interactions between sustained pain signaling in nociceptors and regulation of integrins in those neurons. Although these studies support an emerging schema for integrin-dependent mechanically-induced facet joint pain, work is needed to fully characterize the temporal expression of different integrin subunits in the peripheral terminal of primary afferents in response to tissue injury.…”

“…Increased nerve growth factor (NGF) in the facet joint and upregulation of the prostaglandin E 2 (PGE 2 ) receptor in neurons in the dorsal root ganglion (DRG) accompany behavioral hypersensitivity induced by painful cervical facet joint trauma in the rat. 32,33 Both NGF and PGE 2 are known to mediate inflammatory pain and can induce behavioral sensitivity when injected intradermally. 14,46 Functionally blocking or knocking down certain integrin subunits, such as the integrin subunit 1, has been shown to prevent the pain induced by NGF or PGE 2 14,46 (Figure 1).…”