Whiplash-like facet joint loading initiates glutamatergic responses in the DRG and spinal cord associated with behavioral hypersensitivity

Abstract

The cervical facet joint and its capsule are a common source of neck pain from whiplash. Mechanical hyperalgesia elicited by painful facet joint distraction is associated with spinal neuronal hyperexcitability that can be induced by transmitter/receptor systems that potentiate the synaptic activation of neurons. This study investigated the temporal response of a glutamate receptor and transporters in the dorsal root ganglia (DRG) and spinal cord. Bilateral C6/C7 facet joint distractions were imposed in the rat either to produce behavioral sensitivity or without inducing any sensitivity. Neuronal metabotropic glutamate receptor-5 (mGluR5) and protein kinase C-epsilon (PKCε) expression in the DRG and spinal cord were evaluated on days 1 and 7. Spinal expression of a glutamate transporter, excitatory amino acid carrier 1 (EAAC1), was also quantified at both time points. Painful distraction produced immediate behavioral hypersensitivity that was sustained for 7 days. Increased expression of mGluR5 and PKCε in the DRG was not evident until day 7 and only following painful distraction; this increase was observed in small-diameter neurons. Only painful facet joint distraction produced a significant increase (p<0.001) in neuronal mGluR5 over time, and this increase also was significantly elevated (p ≤ 0.05) over responses in the other groups at day 7. However, there were no differences in spinal PKCε expression on either day or between groups. Spinal EAAC1 expression was significantly increased (p<0.03) only in the nonpainful groups on day 7. Results from this study suggest spinal glutamatergic plasticity is selectively modulated in association with facet-mediated pain.

Whole-body Vibration at Thoracic Resonance Induces Sustained Pain and Widespread Cervical Neuroinflammation in the Rat

“…PKCe is also upregulated in the DRG after painful joint injury, peripheral inflammation, or heat application [16,28,81,93]. In fact, increased PKCe is evident days after WBV in our current study and also after isolated spinal joint injury [28,81], suggesting ongoing pain signaling from the periphery even after trauma is removed (Figs. 3, 4).…”

“…Images (three to six per rat) were cropped (200 9 200 pixels) to include at least 10 nonoverlapping neurons in each section, selected spatially to include the maximum number of cell bodies within the DRG. The percent pixels positive for PKCe per MAP2-positive area was calculated [28,47,81]. The percent of small-diameter (4-20 lm) or medium-diameter (22-40 lm) neurons that were positive for PKCe in each group was also measured [35,81].…”

“…The protein kinase C (PKC) pathway and in particular, the PKCe isoform regulate peripheral nociceptor function [41,77] and contribute to prolonged pain [1,25,26,28,43]. PKCe is responsible for heat and pain sensitivity in peripheral nociceptors [16,93] and, through PKC pathway signaling, also modulates spinal calcitonin gene-related peptide (CGRP) activity [69,74].…”

The Physiological Basis of Cervical Facet-Mediated Persistent Pain: Basic Science and Clinical Challenges

“…In the rat, supraphysiologic (approximately 20%-30%) strains imposed during dynamic facet capsule stretch at a rate of 500%/s, which matches that sustained by humans, 66,90,95,113 consistently induced pain, while those in the physiologic range (approximately 6%-15%) did not induce pain. 19,26,27,29 Of note, the strain magnitudes that induce pain in vivo are lower than the biomechanical strains at failure of the facet capsule, which have been reported at approximately 35% in posterior retraction 84 and approximately 65% in distraction, 108 though large variability exists between subjects. This is not surprising given that complete transection of the capsule, simulating rupture, does not produce sustained pain in vivo.…”

“…12,17,27,41,43,55,57,71 Mechanical stretch of the facet to failure (mean ± SD, 72.9% ± 7.1% strain) produces morphological abnormalities (ie, focal swelling, vacuolations, and terminal retraction balls) in the axons innervating the facet capsule in the goat. 43 However, as described above, subfailure stretch of the facet capsule exceeding physiologic strains is sufficient to damage the ligament's microstructure and induce pain.…”