Changes in substance P and calcitonin gene-related peptide binding in the dorsal horn of rat spinal cord following pronase-induced deafferentation.

Quantitative receptor autoradiography was used to evaluate potential alterations in substance P (SP) and calcitonin gene-related peptide (CGRP) binding in the L4 spinal segment of rats following unilateral poisoning of the sciatic nerve with pronase. Ten days after pronase-induced deafferentation there was a significant increase in SP and CGRP binding in the superficial (I-II) and deeper (II-IV) laminae of the dorsal horn ipsilaterally. Densitometric measurements revealed a 50% return towards normal values for SP binding by 90 days postpronase injection in all laminae examined, while the density of CGRP binding showed a partial return towards normal values for laminae III-IV only. These differential responses may be indicative of the mechanisms underlying pronase-induced peripheral neuropathy.

Deafferentation-induced regulation of AMPA receptors in the spinal cord of the adult rat.

Glutamate released from primary afferents is thought to be involved in mediating spinal reflexes, nociception, and the development and consequent maintenance of hyperalgesia. The role of glutamate is dependent on the distribution and regulation of glutamate receptors in the spinal cord. Due to the numerous glutamate receptor subtypes and their differential physiological profiles, the system is quite complex. Understanding the regulation of the various glutamate receptor subunits may aid in the elucidation of the role of glutamate in somatosensory processing. In this study we found a transient reduction in delta-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptors in the dorsal horn following partial deafferentation. The time course for the alterations of spinal AMPA receptors may correspond to the functional consequence of deafferentation.

Neurotrophin-3 administration attenuates deficits of pyridoxine-induced large-fiber sensory neuropathy.

Chronic treatment of adult rats for 2-3 weeks with high doses of pyridoxine (vitamin B6) produced a profound proprioceptive loss, similar to that found in humans overdosed with this vitamin or treated with the chemotherapeutic agent cisplatin. Pyridoxine toxicity was manifest as deficits in simple and precise locomotion and sensory nerve function and as degeneration of large-diameter/large-fiber spinal sensory neurons. As assessed quantitatively in a beam-walking task and by EMG recording of H waves evoked by peripheral nerve stimulation, coadministration of the neurotrophic factor neurotrophin-3 (NT-3; 5-20 mg . kg-1 . d-1, s.c.) during chronic pyridoxine treatment largely attenuated the behavioral and electrophysiological sequelae associated with pyridoxine toxicity. Furthermore, NT-3 administration prevented degeneration of sensory fibers in the dorsal column of the spinal cord. These data are consistent with the evidence that NT-3 is a target-derived neurotrophic factor for muscle sensory afferents and suggest that pharmacological doses of NT-3 may be beneficial in the treatment of large-fiber sensory neuropathies.

Trophic effect of ciliary neurotrophic factor on denervated skeletal muscle.

The actions and receptor for ciliary neurotrophic factor (CNTF) are largely restricted to cells of the nervous system, although one of the CNTF receptor components, CNTFR alpha, is expressed by skeletal muscle. Here we show that the other CNTF receptor components, LIFR beta and gp130, are also expressed by skeletal muscle and that expression of all three CNTF receptor components is greatly increased in denervated muscle. In vivo, administration of CNTF activates these receptors on skeletal muscle by inducing receptor phosphorylation and immediate-early gene responses. Furthermore, CNTF reduces the denervation-induced atrophy of muscle and attenuates the reduced twitch and tetanic tensions that result from muscle denervation. Our findings reveal that, in addition to its known neurotrophic actions, CNTF exerts myotrophic effects by attenuating the morphological and functional changes associated with denervation of rat skeletal muscle.

The recovery of postural reflexes and locomotion following low thoracic hemisection in adult cats involves compensation by undamaged primary afferent pathways.

Spinal hemisection in the adult cat results in motor impairments followed by substantial recovery of function (16, 20, 39, 53). The present study was undertaken to assess the contribution of undamaged ipsilateral segmental and contralateral descending systems to recovery of motor function. Quantitative behavioral methods were used to examine monopedal reflex and bipedal locomotor functions after thoracic hemisection. Different facets of motor behavior recover at different times. The recovery of monopedal postural reflexes precedes the recovery of more complex motor behavior. Since the reflexes tested are initiated by segmental afferent input and show recovery and normal motor patterns during locomotion, as defined by kinematic analysis show recovery, it is likely that dorsal root input compensates for the loss of descending input to one side of the spinal cord. Quantitative immunocytochemical methods for visualizing the central projections of dorsal root fibers (monoclonal antibody RAT-102; 49) and the descending serotoninergic pathway were used to examine the response of these pathways to hemisection. Hemisection results in a permanent decrease in the density of serotoninergic projections and a permanent increase in dorsal root projections in the spinal cord. The increased density of RAT-102 may represent an increase in the projection of dorsal root fibers and provide the increased input necessary to mediate enhanced reflex control. A transient increase in GAP-43 in the dorsal horn ipsilateral to the hemisection suggests that the increased density of RAT-102 immunoreactivity is associated with growth. Taken together, our results suggest that sprouting of primary afferents within the spinal cord is one mechanism underlying the recovery of function after hemisection.