16 research outputs found

    Partial deletion of p75NTR in large-diameter DRG neurons exerts no influence upon the survival of peripheral sensory neurons in vivo

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    The p75 neurotrophin receptor (p75) is required for maintaining peripheral sensory neuron survival and function; however, the underlying cellular mechanism remains unclear. The general view is that expression of p75 by the neuron itself is required for maintaining sensory neuron survival and myelination in the peripheral nervous system (PNS). Adopting a neuronal-specific conditional knockout strategy, we demonstrate the partial depletion of p75 in neurons exerts little influence upon maintaining sensory neuron survival and peripheral nerve myelination in health and after demyelinating neuropathy. Our data show that the density and total number of dorsal root ganglion (DRG) neurons in 2-month-old mice is not affected following the deletion of p75 in large-diameter myelinating neurons, as assessed by stereology. Adopting experimental autoimmune neuritis induced in adult male mice, an animal model of demyelinating peripheral neuropathy, we identify that deleting p75 in myelinating neurons exerts no influence upon the disease progression, the total number of DRG neurons, and the extent of myelin damage in the sciatic nerve, indicating that the expression of neuronal p75 is not essential for maintaining peripheral neuron survival and myelination after a demyelinating insult in vivo. Together, results of this study suggest that the survival and myelination of peripheral sensory neurons is independent of p75 expressed by a subtype of neurons in vivo. Thus, our findings provide new insights into the mechanism underpinning p75-mediated neuronal survival in the PNS

    The neurochemistry and morphology of functionally identified corneal polymodal nociceptors and cold thermoreceptors

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    <div><p>It is generally believed that the unencapsulated sensory nerve terminals of modality specific C- and Aδ-neurons lack structural specialization. Here we determined the morphology of functionally defined polymodal receptors and cold thermoreceptors in the guinea pig corneal epithelium. Polymodal receptors and cold thermoreceptors were identified by extracellular recording at the surface of the corneal epithelium. After marking the recording sites, corneas were processed to reveal immunoreactivity for the transient receptor potential channels TRPV1 (transient receptor potential cation channel, subfamily V, member 1) or TPRM8 (transient receptor potential cation channel subfamily M member 8). Polymodal receptor nerve terminals (n = 6) were TRPV1-immunoreactive and derived from an axon that ascended from the sub-basal plexus to the squamous cell layer where it branched into fibers that ran parallel to the corneal surface and terminated with small bulbar endings (ramifying endings). Cold thermoreceptor nerve terminals were TRPM8-immunoreactive (n = 6) and originated from an axon that branched as it ascended through the wing cell and squamous cell layers and terminated with large bulbar endings (complex endings). These findings indicate that modality specific corneal sensory neurons with unencapsulated nerve endings have distinct nerve terminal morphologies that are likely to relate to their function.</p></div

    N-Glycosylation determines ionic permeability and desensitization of the TRPV1 capsaicin receptor*

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    The balance of glycosylation and deglycosylation of ion channels can markedly influence their function and regulation. However, the functional importance of glycosylation of the TRPV1 receptor, a key sensor of pain-sensing nerves, is not well understood, and whether TRPV1 is glycosylated in neurons is unclear. We report that TRPV1 is N-glycosylated and that N-glycosylation is a major determinant of capsaicin-evoked desensitization and ionic permeability. Both N-glycosylated and unglycosylated TRPV1 was detected in extracts of peripheral sensory nerves by Western blotting. TRPV1 expressed in HEK-293 cells exhibited various degrees of glycosylation. A mutant of asparagine 604 (N604T) was not glycosylated but did not alter plasma membrane expression of TRPV1. Capsaicin-evoked increases in intracellular calcium ([Ca 2+] i) were sustained in wild-type TRPV1 HEK-293 cells but were rapidly desensitized in N604T TRPV1 cells. There was marked cell-to-cell variability in capsaicin responses and desensitization between individual cells expressing wild-type TRPV1 but highly uniform responses in cells expressing N604T TRPV1, consistent with variable levels of glycosylation of the wild-type channe

    Neurobiology of temporomandibular joint pain: therapeutic implications

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    Persistent pain is the main reason for patient presentation with temporomandibular joint (TMJ) disorders. The pain is thought to result, at least in part, from sensitization of trigeminal sensory neurons that innervate the TMJ region. Sensitized sensory neurons can be hyperexcitable, responding both more readily and more vigorously to peripheral stimuli. At a cellular level, it is the distribution and function of ion channels and receptors that determine neuronal hyperexcitability. Thus, these ion channels and receptors are potential targets for the development of novel therapeutics. In this review, we will explore the role of specific ion channels and receptors that are actively being investigated in preclinical studies, focusing on inflammatory-induced pain of the TMJ, and comment on the therapeutic potential of pharmacological manipulation of these channels and receptors in the treatment of pain associated with TMJ disorders

    Neurochemical classification and projection targets of CART peptide immunoreactive neurons in sensory and parasympathetic ganglia of the head

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    The aims of the present study were to determine if there is neuronal Cocaine and amphetamine regulated transcripts (CART) peptide expression (CART+) in parasympathetic (sphenopalatine (SPG); otic (OG)) and sensory (trigeminal (TG)) ganglia of the head and to examine the neurochemical phenotype (calcitonin gene-related peptide (CGRP), neurofilament 200 (NF200), isolectin B4 (IB4) binding, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY) and enkephalin (ENK) immunoreactivity) and projection targets (lacrimal gland (LG), parotid gland (PG), nasal mucosa (NM), temporomandibular joint (TMJ), middle cerebral artery (MCA) and middle meningeal artery (MMA)) of CART expressing neurons in these ganglia. We found CART+ neurons in both the SPG (5.25 ± 0.07%) and OG (4.32 ± 0.66). A significant proportion of these CART+ neurons contained VIP, NPY or ENK (34%, 26% and 11%, respectively). SPG neurons retrogradely labelled from the lacrimal gland (29%) were CART+, but we were unable to demonstrate CART+ labelling in any of the SPG or OG neurons labelled from other targets. This supports a role for CART peptides in lacrimation or regulation of vascular tone in the lacrimal gland, but not in salivation or nasal congestion. CART+ neurons were also present in the trigeminal ganglion (1.26 ± 0.38%), where their size distribution was confined almost completely to neurons smaller than 800 μm2 (mean = 410 μm2; 98% < 800 μm2), and were almost always CGRP+, but did not bind IB4. This is consistent with a role for CART peptides in trigeminal pain. However, there were few CART+ neurons amongst any of the trigeminal neurons retrogradely labelled from the targets we investigated and thus we cannot comment on the tissue type where such pain may have originated. Our study shows that some specialization of CART peptide expression (based on neurochemical phenotype and target projection) is evident in sensory and parasympathetic ganglia of the head

    The cortical representation of sensory inputs arising from bone

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    In the present study, we show that sensory information from bone reaches the discriminative areas of the somatosensory cortices by electrically stimulating the nerve to the cat humerus and recording evoked potentials on the surface of the primary (SI) and secondary (SII) somatosensory cortex. The SI focus was located over the rostral part of the postcruciate cortex, caudal to the lateral aspect of the cruciate sulcus. The SII focus was identified on the anterior ectosylvian gyrus, lateral to the suprasylvian sulcus. These foci were located adjacent to, or within areas that responded to stimulation of the median, ulnar and/or musculocutaneous nerves. The latency (6–11 ms) to onset of cortical responses in SI and SII were indistinguishable (unpaired t-test; P > 0.05), and were consistent with activation of Aδ fibers in the peripheral nerve. The amplitudes of the cortical responses were graded as a function of stimulus intensity, and may reflect a mechanism for intensity coding. We did not observe long latency cortical responses (50–300 ms) that would be consistent with C fiber activation in the peripheral nerve, and provide evidence that this may be attributable to inhibition of cortical responsiveness following the initial Aδ response. Our finding of discrete, short latency evoked potentials (presumably of Aδ origin) in the primary and secondary somatosensory cortices, following stimulation of a nerve innervating bone, may reflect a mechanism for the discriminative component of bone pain

    Hyperpolarization-activated cyclic-nucleotide gated 4 (HCN4) protein is expressed in a subset of rat dorsal root and trigeminal ganglion neurons

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    Abstract Hyperpolarization-activated cyclic nucleotidegated (HCN) cation channels are active at resting membrane potential and thus are likely to contribute to neuronal excitability. Four HCN channel subunits (HCN1–4) have previously been cloned. The aim of the current study was to investigate the immunoreactivity of HCN4 channel protein in rat trigeminal (TG) and dorsal root ganglion (DRG) sensory neurons. HCN4 was present in 9% of TG neurons and 4.7% of DRG neurons, it was distributed in a discrete population of small-diameter neurons in the TG but was located in cells of all sizes in the DRG. Approximately two thirds of HCN4-containing neurons in each ganglia were labelled with antisera raised against the 200-kDa neurofilament (NF200). The remaining HCN4-containing neurons were NF200-negative, were not labelled with antisera raised against calcitonin-gene related peptide (CGRP), and did not bind the isolectin B4 (IB4). HCN4-containing neurons made up more than half of the population of small-diameter primary afferent neurons that did not contain either NF200 or CGRP or bind IB4 in both TG and DRG. This population was not insignificant, comprising 5% of TG neurons and 2% of DRG neurons.Hyun-jung Cho, Vasiliki Staikopoulos, Jason J. Ivanusic and Ernest A. Jenning

    An intact peripheral nerve preparation for monitoring the activity of single, periosteal afferent nerve fibres

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    A preparation is described in which it is possible to selectively activate and monitor the activity of the individual periosteal afferent nerve fibres arising from the humerus bone of the cat. The nerve is a fine branch of the median nerve that accompanies the small artery and vein that enter the nutrient foramen of the humerus. By freeing this fine nerve from nearby tissue over a length of 1–2 cm and placing it over a silver hook recording electrode, it becomes possible to identify and monitor electrophysiologically, the impulse activity of individual periosteal afferent fibres activated by focal mechanical stimulation of the periosteum. With this preparation it will be possible to examine the central actions and security of transmission at central synaptic targets for single, small-diameter afferent fibres arising from bone

    Mechanosensory perception : are there contributions from bone-associated receptors

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    1. The identity of the receptors and afferent nerve fibres that mediate the sense of touch varies somewhat with body location. Those that have been most intensively characterized are associated with the distal glabrous skin of the limbs and, in primates, mediate the sense of touch in the fingertips and palms. In this glabrous skin region, there appear to be three or four principal classes of tactile sensory nerves that fall into two broad groups. One group, the so-called slowly adapting (SA) receptors and afferent fibres, is responsive to static mechanical displacement of skin tissues and is made up of two classes, the type I (SAI) fibres that innervate Merkel receptors and the type II (SAII) fibres that innervate Ruffini endings. The second broad group displays a pure dynamic sensitivity to tactile stimuli and also falls into two principal classes, the rapidly adapting (RA) tactile fibres that are associated with Meissner corpuscle receptors and the Pacinian corpuscle (PC)-associated class of tactile afferent fibres. 2. In other regions of the skin, such as the hairy skin of the arms, legs and trunk, there are similar functional classes of tactile sensory nerves, although the receptor endings differ somewhat from those of the glabrous skin. 3. Receptors in close association with the long bones of the limbs include groups of Pacinian corpuscles distributed along the interosseous membranes. These are highly sensitive to dynamic forms of mechanical stimuli, in particular vibrotactile disturbances. However, despite their close association with bone, these receptors probably cannot be legitimately considered 'osseoreceptors'. 4. Both the periosteum and the bone marrow are richly supplied by nerve fibres. However, much evidence indicates that these are largely or entirely in the fine-diameter category of nerve fibres, whose roles may be confined to either nociception or to the efferent autonomic regulation of bone-associated blood vessels. 5. In conclusion, it remains uncertain whether any aspects of our innocuous touch or kinaesthetic senses, in either the limbs or in orofacial regions, can be ascribed to 'osseoreceptors' located in the periosteum or within the bone marrow itself
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