Changes in Serotonin, Serotonin Transporter Expression and Serotonin Denervation Supersensitivity: Involvement in Chronic Central Pain after Spinal Hemisection in the Rat

Hains, Bryan C.; Everhart, Alex W.; Fullwood, Steven D.; Hulsebosch, Claire E.

doi:10.1006/exnr.2002.7892

Cited by 133 publications

(84 citation statements)

References 99 publications

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“…5-HT and TH fiber alterations have been correlated to sen- sory, motor, and autonomic disorders (Hains et al, 2002). Initiation of hindlimb movement is influenced by 5-HT activation of motor output via a central pattern generator (Rossignol et al, 1998;Grillner and Wallen, 2002) that organizes automated execution of hindlimb movements.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting Epidermal Growth Factor Receptor Improves Structural, Locomotor, Sensory, and Bladder Recovery from Experimental Spinal Cord Injury

Erschbamer¹,

Pernold²,

Olson³

2007

Journal of Neuroscience

110

104

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Lack of axon regeneration in the adult CNS has been attributed partly to myelin inhibitors and the properties of astrocytes. After spinal cord injury, proliferating astrocytes not only represent a physical barrier to regenerating axons but also express and secrete molecules that inhibit nerve growth, including chondroitin sulfate proteoglycans (CSPGs). Epidermal growth factor receptor (EGFR) activation triggers astrocytes into becoming reactive astrocytes, and EGFR ligands stimulate the secretion of CSPGs as well as the formation of cribriform astrocyte arrangements that contribute to the formation of glial scars. Recently, it was shown that EGFR inhibitors promote nerve regeneration in vitro and in vivo. Blocking a novel Nogo receptor interacting mechanism and/or effects of EGFR inhibition on astrocytes may underlie these effects. Here we show that rats subjected to weight-drop spinal cord injury can be effectively treated by direct delivery of a potent EGFR inhibitor to the injured area, leading to significantly better functional and structural outcome. Motor and sensory functions are improved and bladder function is restored. The robust effects and the fact that other EGFR inhibitors are in clinical use in cancer treatments make these drugs particularly attractive candidates for clinical trials in spinal cord injury.

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Section: Discussionmentioning

confidence: 99%

Inhibiting Epidermal Growth Factor Receptor Improves Structural, Locomotor, Sensory, and Bladder Recovery from Experimental Spinal Cord Injury

Erschbamer¹,

Pernold²,

Olson³

2007

Journal of Neuroscience

110

104

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“…The last four trials were averaged to provide the mean latency of withdrawal. This test has been shown to reveal a reduced latency to foot or tail withdrawal to thermal stimuli in rats with midthoracic hemisections (Hains et al, 2000;Coumans et al, 2001;Hains et al, 2002aHains et al, ,b, 2003bGwak et al, 2004) and cervical partial hemisections (Shumsky et al, 2003) and has been used as a model for neuropathic pain.…”

Section: Immunosuppression With Cyclosporine Amentioning

confidence: 99%

“…Withdrawal of limb or tail during noxious stimulation is an animal model for neuropathic pain (Hains et al, 2000;Lindsey et al, 2000;Coumans et al, 2001;Hains et al, 2002aHains et al, ,b, 2003bShumsky et al, 2003;Gwak et al, 2004), although it is recognized that hyperreflexia is difficult to differentiate from perception of pain in animals. When intense noxious stimulation is used in animals with incomplete lesions, vocalization is often evoked that provides behavioral support for the validity of this model.…”

Section: Recovery Of Sensorimotor Functionmentioning

confidence: 99%

Transplantation of Neuronal and Glial Restricted Precursors into Contused Spinal Cord Improves Bladder and Motor Functions, Decreases Thermal Hypersensitivity, and Modifies Intraspinal Circuitry

Mitsui¹,

Shumsky²,

Lepore³

et al. 2005

J. Neurosci.

168

187

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Transplanting neuronal and glial restricted precursors (NRP/GRP) into a midthoracic injury 9 d after contusion improved bladder and motor function, diminished thermal hypersensitivity, and modified lumbosacral circuitry compared with operated controls (OPcontrols). Histological analysis showed that NRP/GRP survived, filled the lesion site, differentiated into neurons and glia, and migrated selectively. Volume of spinal cord spared was increased in NRP/GRP recipients, suggesting local protection. Bladder areflexia developed in both operated groups, but NRP/GRP recipients exhibited an accelerated recovery, with decreased micturition pressure and fewer episodes of detrusor hyperreflexia. Because noradrenergic receptors proliferate after spinal injury and descending noradrenergic pathways contribute to regulation of bladder control, we examined the effects of administering an ␣-1A-adrenergic antagonist, Tamsulosin, on urodynamics. This improved all cystometric parameters in both operated groups, and micturition pressure in NRP/GRP rats recovered to normal levels. Both operated groups initially showed increased sensitivity to a thermal stimulus applied to the tail; the NRP/GRP rats showed significant improvement over time. NRP/GRP grafts also produced greater recovery of hindlimb function in several tests, although both groups showed persistent and similar deficits in locomotion on a grid.Because bladder, hindlimb, and tail sensory and motor functions are organized through lumbosacral cord, we examined descending and primary afferent projections at L6 -S1. The density of serotonergic, noradrenergic, and corticotrophin releasing factor-positive fibers increased in the NRP/GRP group compared with OP-controls, suggesting some sparing and/or sprouting of these modulatory pathways. Immunocytochemical staining density of dorsal root axons in the dorsal horn increased in the OP-controls but appeared normal in the NRP/GRP group. Synaptophysin immunoreactivity in the lumbosacral dorsal horn was similar among groups, consistent with restoration of synaptic density in both groups of operated animals but by different pathways. We suggest that local protection provided by NRP/GRP resulted in increased sparing/sprouting of descending pathways, which prevented sprouting by dorsal root axons, and that this modification in lumbosacral circuitry contributes to the recovery of function.

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“…Serotonergic projections from the nucleus raphe magnus to the spinal cord synapse in the dorsal horn, causing inhibition or facilitation of pain signaling that depends on the receptor stimulated (Bardin et al, 2000;Calejesan et al, 1998). Thus, loss of descending serotonergic inputs caudal to the lesion site contributes to neuropathic pain (Hains et al, 2002). Serotonergic projections to spinal cord autonomic and motor nuclei are also key regulators of these functions (Chalmers et al, 1985;Saruhashi et al, 1996).…”

Section: Sci Treatment Strategies That Promote Neuroprotectionmentioning

confidence: 99%

The dark side of neuroplasticity

Brown

Weaver

2012

Experimental Neurology

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Whether dramatic or modest, recovery of neurological function after spinal cord injury (SCI) is greatly due to neuroplasticity -the process by which the nervous system responds to injury by establishing new synaptic connections or by altering the strength of existing synapses. However, the same neuroplasticity that allows locomotor function to recover also produces negative consequences such as pain and dysfunction of organs controlled by the autonomic nervous system. In this review we focus specifically on structural neuroplasticity (the growth of new synaptic connections) after SCI and on the consequent development of pain and autonomic dysreflexia, a condition of episodic hypertension. Neuroplasticity after SCI is stimulated by the deafferentation of spinal neurons below the lesion and by the expression of growth-promoting neurotrophins such as nerve growth factor (NGF). A broad range of therapeutic strategies that affect neuroplasticity is being developed for the treatment of SCI. At one end of the spectrum are therapeutic strategies that directly or indirectly increase NGF in the injured spinal cord, and have the most robust effects on neuroplasticity. At the other end of the spectrum are neuroprotective strategies focused on supporting and rescuing uninjured, or partially injured, axons; these might limit the deafferentation stimulus for neuroplasticity. In the middle of this spectrum are strategies that block axon growth inhibitors without necessarily providing a growth stimulus. The literature supports the view that the negative consequences of neuroplasticity develop more commonly with therapies that directly stimulate nerve growth than they develop in the untreated injured cord. Compared to these conditions, neuroplasticity with negative outcomes is less prevalent after treatments that that neutralize axon growth inhibitors, and least apparent after strategies that promote neuroprotection.

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Changes in Serotonin, Serotonin Transporter Expression and Serotonin Denervation Supersensitivity: Involvement in Chronic Central Pain after Spinal Hemisection in the Rat

Cited by 133 publications

References 99 publications

Inhibiting Epidermal Growth Factor Receptor Improves Structural, Locomotor, Sensory, and Bladder Recovery from Experimental Spinal Cord Injury

Inhibiting Epidermal Growth Factor Receptor Improves Structural, Locomotor, Sensory, and Bladder Recovery from Experimental Spinal Cord Injury

Transplantation of Neuronal and Glial Restricted Precursors into Contused Spinal Cord Improves Bladder and Motor Functions, Decreases Thermal Hypersensitivity, and Modifies Intraspinal Circuitry

The dark side of neuroplasticity

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