Simulated Whiplash Modulates Expression of the Glutamatergic System in the Spinal Cord Suggesting Spinal Plasticity Is Associated with Painful Dynamic Cervical Facet Loading

Abstract

The cervical facet joint and its capsule have been reported to be injured during whiplash scenarios and are a common source of chronic neck pain from whiplash. Both the metabotropic glutamate receptor 5 (mGluR5) and the excitatory amino acid carrier 1 (EAAC1) have pivotal roles in chronic pain. In this study, spinal mGluR5 and EAAC1 were quantified following painful facet joint distraction in a rat model of facet-mediated painful loading and were evaluated for their correlation with the severity of capsule loading. Rats underwent either a dynamic C6/C7 joint distraction simulating loading experienced during whiplash (distraction; n = 12) or no distraction (sham; n = 6) to serve as control. The severity of capsular loading was quantified using strain metrics, and mechanical allodynia was assessed after surgery. Spinal cord tissue was harvested at day 7 and the expression of mGluR5 and EAAC1 were quantified using Western blot analysis. Mechanical allodynia following distraction was significantly (p < 0.001) higher than sham. Spinal expression of mGluR5 was also significantly (p < 0.05) greater following distraction relative to sham. However, spinal EAAC1 was significantly (p = 0.0003) reduced compared to sham. Further, spinal mGluR5 expression was significantly positively correlated to capsule strain (p < 0.02) and mechanical allodynia (p < 0.02). Spinal EAAC1 expression was significantly negatively related to one of the strain metrics (p < 0.003) and mechanical allodynia at day 7 (p = 0.03). These results suggest that the spinal glutamatergic system may potentiate the persistent behavioral hypersensitivity that is produced following dynamic whiplash-like joint loading; chronic whiplash pain may be alleviated by blocking mGluR5 expression and/or enhancing glutamate transport through the neuronal transporter EAAC1.

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.…”

“…Rodent studies have shown that varying the severity of the mechanical facet joint injury (ie, the magnitude of facet capsule stretch) directly affects the development and severity of pain symptoms. 29,55 Supraphysiologic capsular stretch matching that of whiplashlike magnitudes is required to induce pain, but stretch at magnitudes comparable to those experienced during physiological joint loading does not induce pain. 28,54 Although capsular stretch induces pain symptoms that are magnitude dependent, 29,55 pain is not further increased if the capsule undergoes failure.…”

“…29,55 Supraphysiologic capsular stretch matching that of whiplashlike magnitudes is required to induce pain, but stretch at magnitudes comparable to those experienced during physiological joint loading does not induce pain. 28,54 Although capsular stretch induces pain symptoms that are magnitude dependent, 29,55 pain is not further increased if the capsule undergoes failure. 53,109 These behavioral studies demonstrate that an intact facet capsule is required for pain development, which supports the notion that afferent fiber signaling is requisite to transmit sensory information from the periphery to the CNS (FIGURE 1).…”

“…While the astroctyic glutamate transporter (glutamate aspartate transporter) is upregulated 1 week after painful injury, both glutamate transporter 1 and excitatory amino-acid carrier 1, which are expressed on other cells, are downregulated, pointing to the widespread and complicated dysregulation of glutamate in pain from facet joint injury. 17,27,29 Nociceptors innervating the facet joint transmit noxious stimuli from peripheral terminals to the spinal cord via action potential propagation. That peripheral inputs lead to increased neuronal firing is evidence of central sensitization (FIGURE 1).…”

Impaired performance on the angle board test is induced in a model of painful whiplash injury but is only transient in a model of cervical radiculopathy

“…8,[10][11][12][13][14][15][16][17] Depending on the cervical level of the affected nerve root in radiculopathy, motor deficits can also be accompanied by weakness of the ipsilateral shoulder and/or arm muscles. 1,18 Our lab has developed separate pain models in the rat that mimic the injury and pain symptoms observed in human neck pain patients with facet-mediated whiplash injuries [19][20][21][22] and cervical radiculopathy. [22][23][24][25] Specifically, distraction of the bilateral facet joints and their capsules that simulates joint loading during whiplash induces significant sustained mechanical allodynia and hyperalgesia in both the shoulders and forepaws.…”