Thrombospondin-4 and excitatory synaptogenesis promote spinal sensitization after painful mechanical joint injury

Abstract

Facet joint injury induces persistent pain that may be maintained by structural plasticity in the spinal cord. Astrocyte-derived thrombospondins, especially thrombospondin-4 (TSP4), have been implicated in synaptogenesis and spinal sensitization in neuropathic pain, but the TSP4 response and its relationship to synaptic changes in the spinal cord have not been investigated for painful joint injury. This study investigates the role of TSP4 in the development and maintenance of persistent pain following injurious facet joint distraction in rats and tests the hypothesis that excitatory synaptogenesis contributes to such pain. Painful facet joint loading induces dorsal horn excitatory synaptogenesis along with decreased TSP4 in the DRG and increased astrocytic release of TSP4 in the spinal cord, all of which parallel the time course of sustained tactile allodynia. Blocking injury-induced spinal TSP4 expression with antisense oligonucleotides or reducing TSP4 activity at its neuronal receptor in the spinal cord with gabapentin treatment both attenuate the allodynia and dorsal horn synaptogenesis that develop after painful facet joint loading. Increased spinal TSP4 also facilitates the development of allodynia and spinal hyperexcitability, even after non-painful physiologic loading of the facet joint. These results suggest that spinal TSP4 plays an important role in the development and maintenance of persistent joint-mediated pain by inducing excitatory synaptogenesis and facilitating the transduction of mechanical loading of the facet joint that leads to spinal hyperexcitability.

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.…”

“…Although basic science studies collectively have defined thresholds for neuronal activation and the induction of pain, those studies are based on work in vivo in the rat and/or goat, or even in artificial constructs simulating the ligament. 14,19,26,27,57,115 Nonetheless, because a common, nondimensional biomechanical metric (strain) has been used across all of those studies, the findings are agnostic of species and/or scale, and it may therefore be possible to extend such findings to the human. The bigger challenges of understanding injury risk and predicting injury in humans are complicated by very complex and integrated systems at play in pain.…”

“…These changes in synapse numbers are accompanied by both increases in the number of spinal cord neurons classified as nociceptive and decreases in the number of neurons classified as low-threshold mechanoreceptors. 19,71 Clinically, these same phenotypic shifts can manifest as decreased pain thresholds to various stimuli. 4 It is important to note that this phenotypic switch is only observed when the strain across the facet capsule exceeds physiological strains and produces pain, 71 further supporting the notion that plastic changes in the spinal cord may also be severity dependent.…”

“…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. 17,19,71 The sustained hyperexcitability of spinal neurons has been speculated to be maintained by structural and/or functional plasticity in the spinal cord. 4,51 Indeed, structural plasticity is evident in the superficial dorsal horn, with approximately a 50% increase in the number of excitatory synapses that are present in the spinal cord, accompanied by a decrease in inhibitory synapses.…”

“…4,51 Indeed, structural plasticity is evident in the superficial dorsal horn, with approximately a 50% increase in the number of excitatory synapses that are present in the spinal cord, accompanied by a decrease in inhibitory synapses. 19,38 This synaptic plasticity can potentiate the excitatory signaling that manifests as hyperalgesia and allodynia. These changes in synapse numbers are accompanied by both increases in the number of spinal cord neurons classified as nociceptive and decreases in the number of neurons classified as low-threshold mechanoreceptors.…”