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Nerve growth factor (NGF) antagonism has long been proposed as a chronic pain treatment. In 2010, the FDA suspended clinical trials using tanezumab, a humanized monoclonal anti-NGF antibody, to treat osteoarthritis due to worsening joint damage in 16 patients. Increased physical activity in the absence of acute pain which normally prevents self-harm was purported as a potential cause. Such an adverse effect is consistent with an extension of tanezumab's primary mechanism of action by decreasing pain sensitivity below baseline levels. In animal inflammatory pain models, NGF antagonism decreases intraepidermal nerve fiber (IENF) density and attenuates increases in expression of nociception-related proteins, such as calcitonin gene-related peptide (CGRP) and substance P (SP). Little is known of the effects of NGF antagonism in noninflamed animals and the hypoalgesia that ensues. In the current study, we immunized rats with NGF or cytochrome C (cytC) and examined (1) nocifensive behaviors with thermal latencies, mechanical thresholds, the hot plate test, and the tail flick test, (2) IENF density, and (3) expression of CGRP, SP, voltage-gated sodium channel 1.8 (Nav1.8), and glutaminase in subpopulations of dorsal root ganglion (DRG) neurons separated by size and isolectin B4 (IB4) labeling. Rats with high anti-NGF titers had delayed responses on the hot plate test but no other behavioral abnormalities. Delayed hot plate responses correlated with lower IENF density. CGRP and SP expression was decreased principally in medium (400-800 μm(2)) and small neurons (<400 μm(2)), respectively, regardless of IB4 labeling. Expression of Nav1.8 was only decreased in small and medium IB4 negative neurons. NGF immunization appears to result in a more profound antagonism of NGF than tanezumab therapy, but we hypothesize that decreases in IENF density and nociception-related protein expression are potential mechanisms for tanezumab-induced hypoalgesia., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Information processing in the inferior colliculus depends on interactions between ascending pathways and intrinsic circuitry, both of which exist within a functional tonotopic organization. To determine how local projections of neurons in the inferior colliculus are related to tonotopy, we placed a small iontophoretic injection of biodextran amine at a physiologically characterized location in the inferior colliculus. We then used electrophysiological recording to place a grid of small deposits of Chicago Sky Blue throughout the same frequency range to specify an isofrequency contour. Using three-dimensional computer reconstructions, we analyzed patterns of transport relative to the physiologically determined isofrequency contour to quantify the extent of the intrinsic connection lamina in all three dimensions. We also performed a quantitative analysis of the numbers of cells in different regions relative to the biodextran amine injection. Biodextran amine-labeled fibers were mainly located dorsomedial to the injection site, confined within the isofrequency contour, but biodextran amine-labeled cells were mainly located ventrolateral to the injection site. When we counted numbers of labeled cells classified by morphological type, we found that both elongate and multipolar cells were labeled within the isofrequency contour. Because the dendrites of multipolar cells typically extend outside the isofrequency lamina, it is likely that they receive input from other isofrequency contours and relay it to more dorsomedial portions of their specific isofrequency contour, along with the frequency-specific projections of the elongate cells. Within a given isofrequency contour, there is a consistent organization in which intrinsic connections ascend from the ventrolateral portion to more dorsomedial points along the contour, forming a cascaded system of intrinsic feedforward connections that seem ideally suited to provide the delay lines necessary to produce several forms of selectivity for temporal patterns in inferior colliculus neurons.

Retrograde, transneuronal tracing with Bartha's strain of pseudorabies virus was used in rats to identify spinal cord, brainstem and hypothalamic loci of uterine-related neurons that could function in the regulation of uterine activity. Based on the premise that estrogen might influence such uterine-related neurons, the existence of estrogen receptors in neurons in these same loci was examined. Viral injections were made into the uterine cervix, body and cervical end of the uterine horns, and the rats allowed to survive for four to six days. After four days, mainly the spinal cord, medulla and pons contained virus-infected neurons. After longer survival times, progressively higher levels of the neuraxis contained viral-labeled neurons, so that by six days hypothalamic uterine-related neurons were identified. First-order virus-infected neurons were visualized by immunohistochemistry in the pelvic paracervical parasympathetic ganglia and in inferior mesenteric sympathetic ganglia. Preganglionic and putative interneurons were labeled in the lumbosacral spinal cord and thoracic spinal cord mainly in the lateral horn area (sacral parasympathetic nucleus and intermediolateral nucleus), lateral aspect of the dorsal horn, intermediate gray, lamina X and dorsal gray commissural area. In the brainstem, labeling was most evident and consistent in the nucleus tractus solitarius, ventrolateral medulla, raphe magnus and pallidus nuclei, parapyramidal area, A5 cell group, Barrington's nucleus of the pons and periaqueductal gray of the midbrain. In the hypothalamus, virus-infected neurons were most marked in the paraventricular nucleus, with fewer in the medial preoptic area and ventromedial hypothalamic nucleus. Estrogen receptor-immunoreactive neurons were most often present among the virus-labeled uterine-related neurons of the spinal cord, nucleus tractus solitarius, ventrolateral medulla, periaqueductal gray, medial preoptic area and ventromedial hypothalamic nucleus. These results identify a multisynaptic pathway of neurons whose eventual output is involved in uterine functions, whose distribution is similar to that revealed by pseudorabies virus tracing from other visceral organs, and which are often mixed among estrogen-responsive neurons.

The central gray region (lamina X) of the lumbar spinal cord in cat was examined by electron microscopy. This region consisted of three morphological zones. Medially, the first zone was comprised of ependyma which surrounded the central canal. The ependyma in the cat spinal cord was similar to most vertebrate spinal ependyma. Secondly, a subependymal zone consisted of glial processes arranged parallel to the long axis of the spinal cord. This glial zone was widest lateral to the central canal and extended approximately 75 microns. The lateral edge of the glial zone intermingled with a neuropil zone, the third zone. The components of the neuropil zone consisted of dendrites, myelinated and unmyelinated axons, synaptic terminals, astrocytes and neurons. The dendrites and neurons generally were oriented parallel with the long axis of the spinal cord. Three synaptic terminal types were categorized according to vesicular morphology, i.e. small round vesicles, flattened vesicles and dense core vesicles. The central gray region has been implicated in nociception and has been shown to receive both primary afferent and supraspinal input. The results from this study are consistent with the central gray region being an area of multiple synaptic inputs which may form the morphological basis of nociceptive processing that ascends to brainstem nuclei.