Predifferentiated GABAergic Neural Precursor Transplants for Alleviation of Dysesthetic Central Pain Following Excitotoxic Spinal Cord Injury

Abstract

Intraspinal quisqualic acid (QUIS) injury induce (i) mechanical and thermal hyperalgesia, (ii) progressive self-injurious overgrooming of the affected dermatome. The latter is thought to resemble painful dysesthesia observed in spinal cord injury (SCI) patients. We have reported previously loss of endogenous GABA immunoreactive (IR) cells in the superficial dorsal horn of QUIS rats 2 weeks post injury. Further histological evaluation showed that GABA-, glycine-, and synaptic vesicular transporter VIAAT-IR persisted but were substantially decreased in the injured spinal cord. In this study, partially differentiated GABA-IR embryonic neural precursor cells (NPCs) were transplanted into the spinal cord of QUIS rats to reverse overgrooming by replenishing lost inhibitory circuitry. Rat E14 NPCs were predifferentiated in 0.1 ng/ml FGF-2 for 4 h prior to transplantation. In vitro immunocytochemistry of transplant cohort showed large population of GABA-IR NPCs that double labeled with nestin but few colocalized with NeuN, indicating partial maturation. Two weeks following QUIS lesion at T12-L1, and following the onset of overgrooming, NPCs were transplanted into the QUIS lesion sites; bovine adrenal fibroblast cells were used as control. Overgrooming was reduced in >55.5% of NPC grafted animals, with inverse relationship between the number of surviving GABA-IR cells and the size of overgrooming. Fibroblast-control animals showed a progressive worsening of overgrooming. At 3 weeks post-transplantation, numerous GABA-, nestin-, and GFAP-IR cells were present in the lesion site. Surviving grafted GABA-IR NPCs were NeuN+ and GFAP−. These results indicate that partially differentiated NPCs survive and differentiate in vivo into neuronal cells following transplantation into an injured spinal cord. GABA-IR NPC transplants can restore lost dorsal horn inhibitory signaling and are useful in alleviating central pain following SCI.

Recombinant neural progenitor transplants in the spinal dorsal horn alleviate chronic central neuropathic pain

“…Fig. 3 indicates a reduction in GABA immunoreactivity in neuronal cell bodies after SCI, similar to reports in other neuropathic pain models (7,18,29,32,36,48). The reduced immunoreactivity is observed mainly at lateral and medial side of the dorsal horn in laminae I-III.…”

“…Previous studies in our laboratory showed amelioration of neuropathic pain in rats induced by either peripheral nerve injury or spinal cord injury by intraspinal GABAergic NPC grafts (42,43,48,49). Potential integration with host dorsal horn neurocircuitry is supported by both electrophysiological (43) and neuroanatomical (7) findings.…”

Alleviation of chronic pain following rat spinal cord compression injury with multimodal actions of huperzine A

“…Such a multimodal modulatory role of HUP-A may provide a strategy for pain management with minimal potential for the development of drug tolerance and dependence. This reasoning is supported by recent studies in which coadministration of the cholinesterase inhibitor donezepil and an initially ineffective dose of the adrenergic analgesic dexmedetomidine elicited antihypersensitivity effects in a rat model of peripheral neuropathic pain (41), and cell transplantation provided GABAergic interneurons that inhibited dysesthetic central pain after excitotoxic SCI (39).…”

“…6 E and F). Cholinergic signaling through mAChRs has been reported to decrease the release of substance P in the rat dorsal spinal cord in response to acute noxious stimulation of the tail (39) and to inhibit pain-transmitting spinothalamic and thalamic neurons (17,40). Although cholinergic agonists for pain control are poorly ; n = 7 per group).…”

The influence of neurotransplantation with different allogenic tissues on the course of the spasticity and chronic pain syndrome after experimental spinal cord injury

“…492-497, 511, 514-519] при спінальній травмі залежить від реалізації компонентів запального процесу, характерного у тому числі для будь-якого нейроінженерного втручання трансплантаційного типу [26,27]. Попри цей оче-видний факт, вивчення впливу таких втручань при спінальній травмі на перебіг синдрому спастичності [28,29] та хронічного больового синдрому [30][31][32][33][34][35][36][37][38][39][40] становить міноритарну частку робіт, присвячених темі відновного лікування спінальної травми. Крім того, очевидним є факт обмеження сучасних нейроінженер-них втручань при спінальній травмі [41][42][43][44]; відсутній порівняльний аналіз їх ефективності на тлі тканинної нейротрансплантації, передусім тих її варіантів, що оперують найбільш місткими джерелами потенційних учасників нейропластичного процесу.…”