Skilled reaching deterioration contralateral to cervical hemicontusion in rats is reversed by pregabalin treatment conditional upon its early administration.

INTRODUCTION: Gabapentinoids are first-line treatments for painful traumatic and nontraumatic central nervous system disorders. Evidence from a large human study suggests that early use of gabapentinoids after spinal cord injury improves motor scores. The underlying mechanism is unknown. OBJECTIVES: We sought to examine the effects of early pregabalin (PGB, a gabapentinoid) treatment on performance in a fine motor task (skilled reaching) after cervical hemicontusion. We also asked whether early PGB administration affected PGB responsiveness later on. METHODS: Rats received C4/5 cervical hemicontusions. Injury severities ranged from 80 to 150 kdyn. We monitored evidence of skin irritation (peri-incisional and elsewhere) and quantified food pellet retrieval using the Montoya staircase test. Behaviours were assessed in rats receiving early (for 3 weeks from injury induction) and/or late (resuming or beginning at week 8) PGB treatment in animals with 150-kdyn injuries. RESULTS: Contralateral skilled reaching waned in control animals with 150-kdyn injuries. This was prevented in animals, which received early PGB as long as treatment continued. Deterioration of skilled reaching was reversed by later (week 8) PGB only in animals that had received early treatment. Ipsilateral reaching impairment was not improved by PGB. Relief of skin irritation verified early PGB efficacy. CONCLUSION: Hemicontusive spinal cord injury produces a contralateral motor phenotype evocative of on-going neuropathic pain. Early PGB preserves sensitivity to subsequent PGB treatment, indicating that motor function is impaired by neuropathic pain and can be improved indirectly by early PGB administration. Direct effects of PGB on motor circuitry cannot be excluded but are not supported by our data.

Neuropathic pain following traumatic spinal cord injury: Models, measurement, and mechanisms.

Neuropathic pain following spinal cord injury (SCI) is notoriously difficult to treat and is a high priority for many in the SCI population. Resolving this issue requires animal models fidelic to the clinical situation in terms of injury mechanism and pain phenotype. This Review discusses the means by which neuropathic pain has been induced and measured in experimental SCI and compares these with human outcomes, showing that there is a substantial disconnection between experimental investigations and clinical findings in a number of features. Clinical injury level is predominantly cervical, whereas injury in the laboratory is modeled mainly at the thoracic cord. Neuropathic pain is primarily spontaneous or tonic in people with SCI (with a relatively smaller incidence of allodynia), but measures of evoked responses (to thermal and mechanical stimuli) are almost exclusively used in animals. There is even the question of whether pain per se has been under investigation in most experimental SCI studies rather than simply enhanced reflex activity with no affective component. This Review also summarizes some of the problems related to clinical assessment of neuropathic pain and how advanced imaging techniques may circumvent a lack of patient/clinician objectivity and discusses possible etiologies of neuropathic pain following SCI based on evidence from both clinical studies and animal models, with examples of cellular and molecular changes drawn from the entire neuraxis from primary afferent terminals to cortical sensory and affective centers. © 2016 Wiley Periodicals, Inc.

Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis.

BACKGROUND: Tamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf3 promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf3 induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently. RESULTS: We found that granular neurons of the olfactory bulb and dentate gyrus, vascular cells and ependymal cells throughout the brain, and peripheral sensory neurons expressed tdtomato in response to TAM treatment. We also show that TAM induced Atf3 up-regulation through inhibition of cholesterol epoxide hydrolase (ChEH): reporter expression was mitigated by delivery in vitamin E-rich wheat germ oil (vitamin E depletes ChEH substrates), and was partially mimicked by a ChEH-specific inhibitor. CONCLUSIONS: This work demonstrates that TAM stresses cells of the adult central and peripheral nervous systems and highlights concerns about clinical and experimental use of TAM. We propose TAM administration in vitamin E-rich vehicles such as wheat germ oil as a simple remedy.