Early afferent activity from the facet joint after painful trauma to its capsule potentiates neuronal excitability and glutamate signaling in the spinal cord

Abstract

Cervical facet joint injury induces persistent pain and central sensitization. Preventing the peripheral neuronal signals that initiate sensitization attenuates neuropathic pain. Yet, there is no clear relationship between facet joint afferent activity, development of central sensitization, and pain, which may be hindering effective treatments for this pain syndrome. This study investigates how afferent activity from the injured cervical facet joint affects induction of behavioral sensitivity and central sensitization. Intra-articular bupivacaine was administered to transiently suppress afferent activity immediately or 4 days after facet injury. Mechanical hyperalgesia was monitored after injury, and spinal neuronal hyperexcitability and spinal expression of proteins that promote neuronal excitability were measured on day 7. Facet injury with saline vehicle treatment induced significant mechanical hyperalgesia (p<0.027), dorsal horn neuronal hyperexcitability (p<0.026), upregulation of pERK1/2, pNR1, mGluR5, GLAST, and GFAP, and downregulation of GLT1 (p<0.032). However, intra-articular bupivacaine immediately after injury significantly attenuated hyperalgesia (p<0.0001), neuronal hyperexcitability (p<0.004), and dysregulation of excitatory signaling proteins (p<0.049). In contrast, intra-articular bupivacaine at day 4 had no effect on these outcomes. Silencing afferent activity during the development of neuronal hyperexcitability (4hr, 8hr, 1 day) attenuated hyperalgesia and neuronal hyperexcitability (p<0.045) only for the treatment given 4 hours after injury. This study suggests that early afferent activity from the injured facet induces development of spinal sensitization via spinal excitatory glutamatergic signaling. Peripheral intervention blocking afferent activity is only effective over a short period of time early after injury and before spinal modifications develop, and is independent of modulating spinal glial activation.

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

“…Bupivacaine attenuated pain symptoms and prevented the development of spinal neuronal hypersensitivity when given immediately after injury, while the same administration at times even as early as 4 days later had no effect on modifying either response compared to the typical injury response. 17 This narrow and early establishment of spinal modifications strongly supports a similarly narrow temporal window for intervention after a whiplash injury during which the onset of spinal mechanisms of sensitization can be prevented. The initial injury-induced hyperexcitability of dorsal horn neurons that develops by 24 hours after injury persists for at least 7 days in the rat.…”

“…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.…”

“…Painful facet injury modifies the spinal expression of a number of nociceptive molecules involved in excitatory glutamatergic signaling, including phosphorylated ERK, mGluR5, PKCε, and ionotropic glutamate receptor N-methyl-D-aspartate subunit. 17,27,105 Expression of each of these nociceptive molecules is increased in the spinal cord along the same time course as sustained pain symptoms and spinal hyperexcitability. 17,27,105 In addition to increases in expression of glutamate receptors, expression of glutamate transporters on astrocytes and neurons, which regulate the clearance of glutamate away from synapses, like glutamate aspartate transporter, glutamate transporter 1, and excitatory amino-acid carrier 1, is also altered in the spinal cord 1 week after painful facet stretch.…”

“…17,27,105 Expression of each of these nociceptive molecules is increased in the spinal cord along the same time course as sustained pain symptoms and spinal hyperexcitability. 17,27,105 In addition to increases in expression of glutamate receptors, expression of glutamate transporters on astrocytes and neurons, which regulate the clearance of glutamate away from synapses, like glutamate aspartate transporter, glutamate transporter 1, and excitatory amino-acid carrier 1, is also altered in the spinal cord 1 week after painful facet stretch. 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.…”

“…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).…”