Sensory neurons with cell bodies situated in dorsal root ganglia convey information from external or internal sites of the body such as actual or potential harm, temperature or muscle length to the central nervous system. In recent years, large investigative efforts have worked toward an understanding of different types of DRG neurons at transcriptional, translational, and functional levels. These studies most commonly rely on data obtained from laboratory animals. Human DRG, however, have received far less investigative focus over the last 30 years. Nevertheless, knowledge about human sensory neurons is critical for a translational research approach and future therapeutic development. This review aims to summarize both historical and emerging information about the size and location of human DRG, and highlight advances in the understanding of the neurochemical characteristics of human DRG neurons, in particular nociceptive neurons.

Neurons extend their dendrites and axons to build functional neural circuits, which are regulated by both positive and negative signals during development. Brain-derived neurotrophic factor (BDNF) is a positive regulator for neurite outgrowth and neuronal survival but the functions of its precursor (proBDNF) are less characterized. Here we show that proBDNF collapses neurite outgrowth in murine dorsal root ganglion (DRG) neurons and cortical neurons by activating RhoA via the p75 neurotrophin receptor (p75NTR). We demonstrated that the receptor proteins for proBDNF, p75NTR and sortilin, were highly expressed in cultured DRG or cortical neurons. ProBDNF caused a dramatic neurite collapse in a dose-dependent manner and this effect was about 500 fold more potent than myelin-associated glycoprotein. Neutralization of endogenous proBDNF by using antibodies enhanced neurite outgrowth in vitro and in vivo, but this effect was lost in p75NTR^−/− mice. The neurite outgrowth of cortical neurons from p75NTR deficient (p75NTR^−/−) mice was insensitive to proBDNF. There was a time-dependent reduction of length and number of filopodia in response to proBDNF which was accompanied with a polarized RhoA activation in growth cones. Moreover, proBDNF treatment of cortical neurons resulted in a time-dependent activation of RhoA but not Cdc42 and the effect was absent in p75NTR^−/− neurons. Rho kinase (ROCK) and the collapsin response mediator protein-2 (CRMP-2) were also involved in the proBDNF action. proBDNF has an opposing role in neurite outgrowth to that of mature BDNF. Our observations suggest that proBDNF collapses neurites outgrowth and filopodial growth cones by activating RhoA through the p75NTR signaling pathway.

The actions of different cholinergic agonists and antagonists were investigated on nociceptive afferents using the rat skin–saphenous nerve preparation,in vitro. Nicotine was able to weakly excite C-nociceptors and to induce a mild sensitization to heat stimulation (in 77% of tested fibers) in a dose-dependent manner (10⁻⁶to 10⁻⁵m), but it caused no alteration in mechanical responsiveness tested with von Frey hairs. Muscarine did not induce a significant nociceptor excitation, but almost all fibers exhibited a marked desensitization to mechanical and heat stimuli in a dose-dependent manner (from 10⁻⁶to 10⁻⁴m). The muscarinic effects could be prevented by the general muscarinic antagonist scopolamine (10⁻⁵m), by the M3 antagonist 1,1-dimethyl-4-diphenylacetoxypiperidium oxide (10⁻⁶m) co-applied with the M2 antagonist gallamine (10⁻⁵m), and by gallamine alone. As positive control we used the relatively M2-selective agonist arecaidine (10⁻⁶to 10⁻⁵m), obtaining a similar desensitizing effect as with muscarine. Finally, we performed an immunocytochemical study that demonstrated the presence of M2 but not M3 receptors in thin epidermal nerve fibers of the rat hairy skin. Altogether, these data demonstrate opposite effects of nicotinic and muscarinic receptor stimulation on cutaneous nociceptors. M2 receptor-mediated depression of nociceptive responsiveness may convey a therapeutic, i.e., analgesic or antinociceptive, potential.

In the airways, increases in cholinergic nerve activity and cholinergic hypersensitivity are associated with chronic obstructive pulmonary disease and asthma. However, the contribution of individual muscarinic acetylcholine receptor subtypes to the constriction of smaller intrapulmonary airways that are primarily responsible for airway resistance has not been analyzed. To address this issue, we used videomicroscopy and digital imaging of precision-cut lung slices derived from wild-type mice and mice deficient in either the M₁ (mAChR1^-/- mice), M₂ (mAChR2^-/- mice), or M₃ receptor subtype (mAChR3^-/- mice) or lacking both the M₂ and M₃ receptor subtypes (mAChR2/3^-/- double-knockout mice). In peripheral airways from wild-type mice (mAChR^+/+ mice), muscarine induced a triphasic concentration-dependent response, characterized by an initial constriction, a transient relaxation, and a sustained constriction. The bronchoconstriction was diminished by up to 60% in mAChR3^-/- lungs and was completely abolished in mAChR2/3^-/- lungs. The sustained bronchoconstriction was reduced in mAChR2^-/- bronchi, and, interestingly, the transient relaxation was absent; the bronchoconstriction in response to 10^-8 M muscarine was increased by 158% in mAChR1^-/- mice. Quantitative reverse transcriptase-polymerase chain reaction analysis revealed that the disruption of specific mAChR genes had no significant effect on the expression levels of the remaining mAChR subtypes. These results demonstrate that cholinergic constriction of murine peripheral airways is mediated by the concerted action of the M₂ and M₃ receptor subtypes and suggest the existence of pulmonary M₁ receptor activation, which counteracts cholinergic bronchoconstriction. Given the important role of muscarinic cholinergic mechanisms in pulmonary disease, these findings should be of considerable therapeutic relevance.

The biological principles that underlie the induction and process of alveolization in the lung as well as the maintenance of the complex lung tissue structure are one of the major obstacles in pulmonary medicine today. Bone marrow–derived cells have been shown to participate in angiogenesis, vascular repair, and remodeling of various organs. We addressed this phenomenon in the lung vasculature of mice in a model of regenerative lung growth. C57BL/6 mice were transplanted with bone marrow from one of three different reporter gene–transgenic strains. flk-1 ^+/lacZ mice, tie-2/lacZ transgenic mice (both exhibiting endothelial cell–specific reporter gene expression), and ubiquitously enhanced green fluorescent protein (eGFP)-expressing mice served as marrow donors. After hematopoietic recovery, compensatory lung growth was induced by unilateral pneumonectomy and led to complete restoration of initial lung volume and surface area. The lungs were consecutively investigated for bone marrow–derived vascular cells by lacZ staining and immunohistochemistry for phenotype identification of vascular cells. lacZ- or eGFP-expressing bone marrow–derived endothelial cells could not be found in microvascular regions of alveolar septa. Single eGFP-positive endothelial cells were detected in pulmonary arteries at very low frequencies, whereas no eGFP-positive vascular smooth muscle cells were observed. In conclusion, we demonstrate in a model of lung growth and alveolization in adult mice the absence of significant bone marrow–derived progenitor cell contribution to the concomitant vascular growth and remodeling processes.