Intralesion transplantation of serotonergic precursors enhances locomotor recovery but has no effect on development of chronic central pain following hemisection injury in rats

Transient Blockade of the CD11d/CD18 Integrin Reduces Secondary Damage after Spinal Cord Injury, Improving Sensory, Autonomic, and Motor Function

“…Disruption of this modulation by SCI creates an opportunity for exaggerated transmission of pain sensation, including mechanical allodynia. Studies in cord-injured rats have identified several drugs that have short-lived effects on, but do not relieve, chronic allodynia (Xu et al, 1992;Hains et al, 2002). In contrast, our anti-inflammatory treatment had substantial long-lasting effects that limited the mechanical allodynia.…”

Subarachnoid Transplant of the Human Neuronal hNT2.19 Serotonergic Cell Line Attenuates Behavioral Hypersensitivity without Affecting Motor Dysfunction after Severe Contusive Spinal Cord Injury

“…Even though multipotentiality of phenotype expression might be an advantage in a clinical use where the therapeutic mechanism-of-action is unknown (i.e., transplant of NT2-N neurons for stroke [31]), a single, more pure phenotype, such as that for 5HT, could be preferable for use in conditions such as neuropathic pain or motor dysfunction following SCI. Graft of 5HT-secreting cells (using a rat cell line) near the spinal cord has been demonstrated to attenuate neuropathic pain after SCI by restoring spinal 5HT and upregulating spinal BDNF, and downregulating the 5HT transporter [8], but effects on the sensory system require a subarachnoid graft location [33], since apparently, in those studies, an intralesion graft site helps restore motor function. We have seen similar results with the use of intraspinal hNT2.19 grafts and the severe contusive SCI model [23].…”

“…Grafts of cells that release 5HT into the intrathecal space following dorsal hemisection restore spinal 5HT in the dorsal horn [8], increasing 5HT in the CSF, and correct membrane hyperexcitability and phenotype shifts of dorsal horn neurons [9] associated with tactile allodynia and thermal hyperalgesia following SCI. These same 5HT rat cell line grafts are not antinociceptive when placed within the cord, rather than a subarachnoid location, in the same injury paradigm [33], arguing for a focal application of serotonin to/near the dorsal horn (e.g., the subarachnoid space), without further disturbance to the cord, that is required for an only-antinociceptive strategy with a cell therapy approach.…”

“…Following spinal transection, rhythmic locomotor function and increased responsiveness to reflex testing can be restored by transplant of embryonic serotonergic raphe cells [86], presumably by replacement of synaptic connections to motor neurons and release of 5HT in the immediate environment [87]. Our earlier published data indicates that, using grafts of rat 5HT cells derived from an immortalized 5HT cell line [5], locomotor function can only be improved after SCI when grafts are placed within the cord; the same grafts effective for nociception are only effective when placed in the subarachnoid space [33], by attenuating the neuronal hyperexcitability induced by SCI in the dorsal horn [9]. The effects on motor neurons by 5HT-secreting intraspinal grafts are presumably by increasing excitability of host neurons through increases in amplitude of monosynaptic reflexes in the central pattern generator circuitry [88], given the excitatory role of 5HT in the ventral horn [83], as opposed to the indirect inhibitory role for 5HT in the dorsal sensory horn system [89].…”

“…From the variety of phenotypes expressed after differentiation from NT2 cell line, we sought to subclone a human neural cell line from the NT2 heritage that was specific to the synthesis and secretion of 5HT, to characterize these cells in vitro and test their ability to affect nociceptive and motor function in a SCI-pain/motor model. We have previously described the use of 5HT cell therapy with a rat cell line that is able to consistently reverse neuropathic pain after a partial nerve injury [7] and hemisection SCI [33]. Here we expand on our previous investigations [23] with human hNT2.19 5HT-secreting cell grafts in the severe contusion SCI model of chronic pain and motor dysfunction and report findings with human neuronal 5HT cell therapy, where hNT2.19 subarachnoid grafts are able to significantly reduce behavioral hypersensitivity, but not motor dysfunction.…”