Gabapentin for spasticity and autonomic dysreflexia after severe spinal cord injury.

STUDY DESIGN: Using a complete transection spinal cord injury (SCI) model at the fourth thoracic vertebral level in adult rats, we evaluated whether blocking noxious stimuli below the injury diminishes abnormal somatic and autonomic motor reflexes, manifested in muscular spasticity and hypertensive autonomic dysreflexia, respectively. Gabapentin (GBP) is well tolerated and currently used to manage neuropathic pain in the SCI population; evidence suggests that it acts to decrease presynaptic glutamate release. As clinical evidence indicates that GBP may suppress muscular spasticity in the chronic SCI population, we hypothesized that preventing neurotransmission of noxious stimuli with GBP eliminates a critical physiological link to these distinct, debilitating SCI-induced secondary impairments. OBJECTIVES: Behavioural assessments of tail muscle spasticity and mean arterial blood pressure responses to noxious somatic and/or visceral stimulation were used to test the effects of GBP on these abnormal reflexes. SETTING: Lexington, Kentucky. METHODS: We used femoral artery catheterization and radio-telemetric approaches to monitor blood pressure alterations in response to noxious colorectal distension (CRD) weeks after complete SCI. RESULTS: At 2-3 weeks post-SCI, acute GBP administration (50 mg kg(-1), i.p.) significantly attenuated both autonomic dysreflexia and tail spasticity induced by noxious stimuli compared with saline-treated cohorts. CONCLUSION: These results show, for the first time, that a single-pharmacological intervention, GBP, can effectively attenuate the manifestation of both muscular spasticity and autonomic dysreflexia in response to noxious stimuli.

Gabapentin suppresses spasticity in the spinal cord-injured rat.

UNLABELLED: Spasticity poses a major detrimental impact on the quality of life in a significant number of people with spinal cord injury (SCI). Recent observations in our laboratory suggest that spinal transection at the sacral S(2) level induces a significant increase in glutamatergic input to sacrocaudal motoneurons during the time spasticity is present in the tail muscles. The present study examined the efficacy of gabapentin, an agent that has been shown to reduce glutamate release, in managing spasticity within the tail musculature. METHOD: In this blinded, crossover study adult Sprague-Dawley rats with S(2) spinal transections were tested behaviorally for the progression of spasticity in the tail musculature using our established system. When the animals demonstrated a significant level of spastic behavior (e.g. increased response to quick stretch, noxious and non-noxious cutaneous stimuli), they received either saline or the antiepileptic agent gabapentin (GBP; 50 mg/kg i.p.) and were assessed behaviorally and electrophysiologically at 1, 3, 6, 12 and 24 h post-injection. RESULTS: Both spastic behavior and electromyography (EMG) activity were significantly decreased at 1 and 3 h post-GBP injection when compared with the activity level following administration of saline. Spastic behavior and EMG activity gradually increased over time and returned to baseline activity by 24 h post-injection. CONCLUSION: Gabapentin diminishes both the behavioral and electrophysiological manifestation of SCI-induced spasticity, in the tail musculature, in a time dependent manner.

Epithelial overexpression of BDNF or NT4 disrupts targeting of taste neurons that innervate the anterior tongue.

Brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4) are essential for the survival of geniculate ganglion neurons, which provide the sensory afferents for taste buds of the anterior tongue and palate. To determine how these target-derived growth factors regulate gustatory development, the taste system was examined in transgenic mice that overexpress BDNF (BDNF-OE) or NT4 (NT4-OE) in basal epithelial cells of the tongue. Overexpression of BDNF or NT4 caused a 93 and 140% increase, respectively, in the number of geniculate ganglion neurons. Surprisingly, both transgenic lines had severe reduction in fungiform papillae and taste bud number, primarily in the dorsal midregion and ventral tip of the tongue. No alterations were observed in taste buds of circumvallate or incisal papillae. Fungiform papillae were initially present on tongues of newborn BDNF-OE animals, but many were small, poorly innervated, and lost postnatally. To explain the loss of nerve innervation to fungiform papillae, the facial nerve of developing animals was labeled with the lipophilic tracer DiI. In contrast to control mice, in which taste neurons innervated only fungiform papillae, taste neurons in BDNF-OE and NT4-OE mice innervated few fungiform papillae. Instead, some fibers approached but did not penetrate the epithelium and aberrant innervation to filiform papillae was observed. In addition, some papillae that formed in transgenic mice had two taste buds (instead of one) and were frequently arranged in clusters of two or three papillae. These results indicate that target-derived BDNF and NT4 are not only survival factors for geniculate ganglion neurons, but also have important roles in regulating the development and spatial patterning of fungiform papilla and targeting of taste neurons to these sensory structures.

Level of p75 receptor expression in sensory ganglia is modulated by NGF level in the target tissue.

Neurotrophins play an essential role in sensory development by providing trophic support to neurons that innervate peripheral targets. Nerve growth factor (NGF), neurotrophin-3, neurotrophin-4, and brain-derived neurotrophin exert their survival effect by binding to two transmembrane receptor types: trk receptors, which exhibit binding specificity, and the p75NTR receptor, which binds all neurotrophins. To determine how target-derived neurotrophins affect sensory neuron development and function, we used transgenic mice that overexpress NGF in the skin to examine the impact of NGF overexpression on receptor expression. Previous studies of trk expression in trigeminal ganglia of adult NGF transgenics showed that the percentage of trkA neurons doubled and their number increased fivefold. The present study focused on the p75 receptor and shows that the percentage of neurons expressing p75NTR also increase in NGF ganglia, but only by 10%. This increase did not encompass the small, BS-IB-4 isolectin-positive cells as they remained p75 negative in transgenic ganglia. Interestingly, levels of trkA protein were not increased on a per-cell level, whereas levels of p75NTR increased nearly threefold. These results show that in sensory systems, target-derived NGF modulates the level of p75NTR receptor expression, and in so doing, may act to regulate the formation of functional receptor complexes and subsequent trophic action.

The physiological effects of serotonin on spontaneous and amino acid-induced activation of cerebellar nuclear cells: an in vivo study in the cat.

It is well established that cerebellar efferents originate from neurons located within the cerebellar nuclei. Neurons within these nuclei receive excitatory inputs derived from the axons that arise from cells in several different regions of the brainstem and spinal cord, some of which continue on to terminate as mossy fibers and climbing fibers in the cerebellar cortex. GABA-induced inhibition in the nuclei is derived primarily from Purkinje cells located in the overlying cortex and possibly from axonal collaterals of a population of small, GABAergic nuclear neurons. In addition, a third chemically defined system of afferents that contain the monoamine serotonin forms a dense plexus of fibers throughout the cat's cerebellar nuclei. The intent of this study is to determine the physiological effects of serotonin on the spontaneous activity of cerebellar nuclear cells as well as that induced by application of the excitatory amino acids glutamate and aspartate in an adult in vivo preparation. Iontophoretic application of serotonin in anesthetized preparations suppresses both spontaneous and excitatory amino acid induced activity. In addition, interactions between serotonin and the amino acid analogs quisqualate and NMDA were analyzed; 5HT suppresses the excitatory responses of neurons to both analogs. However, there is a stronger suppressive effect on quisqualate-induced excitation as compared to that elicited by NMDA. In addition to modulating the effects of the excitatory amino acids, serotonin also potentiates the inhibitory effects of GABA. However, the effect was greatest if the neuron was initially preconditioned with GABA. In summary, serotonin acts to suppress amino acid induced activity in cerebellar nuclear neurons and to enhance gABA-mediated inhibition. The net effect is a decrease in nuclear cell activity and consequently in cerebellar output.

The origin of serotoninergic afferents to the cat's cerebellar nuclei.

In the cat, serotoninergic (5HT) axons and terminals form a dense plexus that is present throughout the granule cell and Purkinje cell layers of the cerebellar cortex and all of the cerebellar nuclei. The intent of the present study was to identify the source of 5HT fibers in the cerebellar nuclei. The medial, interposed, and lateral cerebellar nuclei were selectively injected with either rhodamine or fluorescein-labeled latex microspheres that were retrogradely transported to brainstem neurons. Transverse sections of the brainstem were processed with a primary antibody to 5HT and secondary antibody tagged with either rhodamine or fluorescein. The location of neurons containing both serotonin-like immunoreactivity and retrogradely transported microspheres was plotted. All three of the cerebellar nuclei receive 5HT afferents from the nucleus locus coeruleus, the dorsal raphe nucleus, and the dorsal tegmental nucleus. In addition, the medial nucleus receives projections from the superior central nucleus, the nucleus raphe obscurus, the nucleus raphe magnus, and the periolivary reticular formation. The interposed nuclei receive additional projections from the nucleus raphe magnus, whereas the lateral nucleus receives additional projections from the superior central nucleus. In conclusion, the 5HT projections to the cerebellar nuclei do not appear to be collaterals of those projecting to the cortex (Kerr and Bishop, J Comp Neurol 304:502-515, 1991). These findings suggest that, although the cortex and nuclei are anatomically and physiologically related, they do not process all information in parallel.

In-vitro effects of angiotensin II on steroid production by hamster ovarian follicles and on ultrastructure of the theca interna.

Angiotensin II (AII) is present in the mammalian ovary and has been correlated with atresia in follicles. Since the theca interna may be one site at which atresia is initiated, we wished to determine whether AII exerts an effect on theca interna from explanted ovarian follicles of hamsters. Hamsters were sacrified on the morning of proestrus, and ovaries were removed. Preovulatory follicles were excised from the ovaries, and cultured with one of the following components: medium alone (control); medium plus AII (1 x 10(-6) M); the AII-receptor antagonist [Sar1, Ile8] AII (1 x 10(-4) M); or AII plus antagonist. After 72 h, the follicles were processed for transmission electron microscopy (to determine quantities of theca interna organelles involved in the steroid synthetic pathway) or for protein determination (to normalize steroid production rates). The incubation medium was drawn off and analyzed by radioimmunoassay for progesterone, androstenedione, or estradiol-17 beta. There was a significant positive correlation (r = 0.92, P less than 0.01) between follicular androstenedione secretion and area comprising theca interna smooth endoplasmic reticulum. In the theca interna, AII induced a two-fold and 1.6-fold increase in lipid droplet number and area comprising smooth endoplasmic reticulum, respectively (P less than 0.05). Excess antagonist negated the increase in cell organelles and also reduced androstenedione secretion compared with AII alone (P less than 0.05). Most importantly, AII significantly augmented the ratio of androstenedione:estradiol-17 beta secretion by 44% over that of control. The ultrastructural changes observed in this study and the increase in the androstenedione:estradiol-17 beta production ratio are consistent with atresia-like changes in ovarian follicles.(ABSTRACT TRUNCATED AT 250 WORDS)