Binding sites for the plant lectin Bandeiraea simplicifolia I-isolectin B4 are expressed by nociceptive primary sensory neurones

doi:10.1016/S0006-8993(01)02750-0

Brain Research

Volume 911, Issue 1, 17 August 2001, Pages 101-104

https://doi.org/10.1016/S0006-8993(01)02750-0 Get rights and content

Abstract

Circumstantial evidence suggests that binding sites for the plant lectin Bandeiraea simplicifolia I-isolectin B₄ are expressed by nociceptive primary sensory neurones. In order to test this hypothesis directly, we have used a combination of intracellular staining of functionally characterised primary sensory neurones and lectin binding. Consistent with the hypothesis, none of the low threshold primary sensory neurones we sampled expressed lectin binding sites, whilst a subpopulation of the nociceptive neurones did.

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Acknowledgements

This study was suported by a QUT REA Grant to M.B.P. and an Australian Postgraduate Award to M.B.G.

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NPR-B immunoreactivity was also found in IB4-positive small neurons. It is known that IB4 is expressed by small DRG neurons, nociceptor neurons, which are involved in transmission of thermal, mechanical, and chemical stimuli [12,13], and BNP is also expressed in IB4-positive neurons [31]. In addition, BNP suppresses the excitability of small DRG neurons and reduces inflammatory pain by activating the NPR-A pathway [31].
C-type natriuretic peptide (CNP) is an abundant neuropeptide in the central nervous system, which exerts its physiological effects through natriuretic peptide receptor B (NPR-B). Recently, the CNP/NPR-B system has been recognized as an important regulator for the development of sensory axons. The dorsal root ganglion (DRG) contains neurons transmitting several kinds of spinal sensory stimuli to the central nervous system. In this study, we characterized NPR-B receptor expression in the rat DRG, using reverse transcription-polymerase chain reaction, Western blotting and immunohistochemistry. Immunostaining revealed that NPR-B was expressed in neuronal cell bodies and processes of the DRG, with NPR-B immunoreactivity mainly prominent in small and medium-sized DRG neurons. Double-immunolabeling showed that NPR-B was expressed in calcitonin gene-related peptide- and isolectin B4-positive neurons. Furthermore, NPR-B expression was co-localized with calcitonin gene-related peptide in the dorsal horn of the spinal cord. Together, our data suggest that the natriuretic peptides may perform several biological actions on sensory neurons via their binding to NPR-B in the DRG.
Specific functioning of Cav3.2 T-type calcium and TRPV1 channels under different types of STZ-diabetic neuropathy
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Therefore, we checked whether different types of PDN were associated with changes in a proportion of nonpeptidergic versus peptidergic C-type nociceptors. Using isolectin B4 (IB4) [50] for in vitro labeling of nonpeptidergic neurons [34], small DRG neurons (n = 608), considered as C-type nociceptors [51], were divided into three classes based on the intensity of IB4 binding [43]: strongly IB4-positive, weakly IB4-positive and IB4-negative. Fractions of these neuronal classes were unchanged in all PDN groups compared to control (p > 0.05, χ2-test; Fig. 2).
Streptozotocin (STZ)-induced type 1 diabetes in rats leads to the development of peripheral diabetic neuropathy (PDN) manifested as thermal hyperalgesia at early stages (4th week) followed by hypoalgesia after 8 weeks of diabetes development. Here we found that 6–7 week STZ-diabetic rats developed either thermal hyper- (18%), hypo- (25%) or normalgesic (57%) types of PDN. These developmentally similar diabetic rats were studied in order to analyze mechanisms potentially underlying different thermal nociception. The proportion of IB4-positive capsaicin-sensitive small DRG neurons, strongly involved in thermal nociception, was not altered under different types of PDN implying differential changes at cellular and molecular level. We further focused on properties of T-type calcium and TRPV1 channels, which are known to be involved in Ca^2 + signaling and pathological nociception. Indeed, TRPV1-mediated signaling in these neurons was downregulated under hypo- and normalgesia and upregulated under hyperalgesia. A complex interplay between diabetes-induced changes in functional expression of Cav3.2 T-type calcium channels and depolarizing shift of their steady-state inactivation resulted in upregulation of these channels under hyper- and normalgesia and their downregulation under hypoalgesia. As a result, T-type window current was increased by several times under hyperalgesia partially underlying the increased resting [Ca^2 +]_i observed in the hyperalgesic rats. At the same time Cav3.2-dependent Ca^2 + signaling was upregulated in all types of PDN. These findings indicate that alterations in functioning of Cav3.2 T-type and TRPV1 channels, specific for each type of PDN, may underlie the variety of pain syndromes induced by type 1 diabetes.
GRK2 in sensory neurons regulates epinephrine-induced signalling and duration of mechanical hyperalgesia
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Our data show that the percentages of neurons of all sizes do not differ among genotypes. Small-sized primary sensory neurons have been reported to selectively express IB4 binding sites [8], and relatively high IB4 binding is specific for C-nociceptor-type neurons [7]. When analysing the percentage of IB4(+) and IB4(−) DRG neurons in WT and GRK2-deficient mice, we found that there was no difference in the percentage of IB4(+) neurons.
Epinephrine (EPI) contributes to hyperalgesia in inflammatory and stress conditions. EPI signals via adrenoceptors, which are regulated by G protein-coupled receptor kinase 2 (GRK2). We previously reported that GRK2 is decreased in nociceptors during chronic inflammation. Herein, we investigated whether GRK2 modulates EPI-induced mechanical and thermal hyperalgesia by using GRK2^+/− mice, which express 50% of the GRK2 protein. We demonstrate for the first time that EPI-induced mechanical as well as thermal hyperalgesia is prolonged to approximately 21 days in GRK2^+/− mice, whereas it lasts only 3 to 4 days in wild-type mice. Using cell- specific GRK2-deficient mice, we further show that a low level of GRK2 in primary sensory neurons is critical for this prolongation of EPI-induced hyperalgesia. Low GRK2 in microglia had only a small effect on EPI-induced hyperalgesia. Low GRK2 in astrocytes did not alter EPI-induced hyperalgesia. EPI-induced hyperalgesia was prolonged similarly in mice with tamoxifen-induced homozygous or heterozygous deletion of GRK2. In terms of EPI signalling pathways, the protein kinase A (PKA) inhibitor H-89 inhibited EPI-induced mechanical hyperalgesia in wild-type mice, whereas H-89 had no effect in mice with low GRK2 in sensory neurons (SNS-GRK2^+/− mice). Conversely, intraplantar injection of the protein kinase Cε PKCε inhibitor TAT-PKC_εv1-2 inhibited hyperalgesia in sensory neuron specific (SNS)-GRK2^+/− mice and not in wild-type mice. These results indicate that low GRK2 in primary sensory neurons switches EPI-induced signalling from a protein kinase A-dependent toward a PKCε-dependent pathway that ultimately mediates prolonged EPI-induced hyperalgesia.
Chloride transporters in presynaptic inhibition, pain and neurogenic inflammation
2010, Physiology and Pathology of chloride transporters and channels in the nervous system
This chapter focuses on the chloride transporters in presynaptic and primary sensory neurons (PSNs). PSNs are the cells that convey virtually all somatic and visceral information to the spinal cord and brainstem. The peripheral processes of PSNs collect information from somatic (skin, muscles and joints) and visceral sensory receptors. Their central processes conduct these signals into the spinal cord and brainstem where their central terminals make synapses with higher order neurons. Within the spinal cord and brainstem, these central terminals are subject to significant GABAergic presynaptic control, a crucial mechanism in gating the flow of nociceptive and other sensory information. The chapter also examines the cellular and molecular basis of presynaptic inhibition and PAD. The described basis are: adult primary sensory neurons are depolarized by GABA over their entire surface membrane due to an outward Clˉ gradient, functional significance of the outward Clˉ gradient in the central terminals of primary afferent neurons: PAD and presynaptic inhibition, the GABA-mediated PAD is determined by the magnitude of the outward Clˉ gradient across the plasma membrane of PSNs, and many more.
Glial cell line-derived neurotrophic factor acutely modulates the excitability of rat small-diameter trigeminal ganglion neurons innervating facial skin
2010, Brain, Behavior, and Immunity
Citation Excerpt :
In addition, the expression of GDNF receptors, and in particular GFRα-1 immunoreactivity, was also seen in small-diameter DRG neurons, and corresponded to those which bind the nociceptive marker, IB4, which is believed to be involved in nociceptive function (Silverman and Kruger, 1988; Akkina et al., 2001; Bennett et al., 1998; Molliver et al., 1997; Leitner et al., 1999). In fact, most IB4 positive nociceptors are sensitive to noxious mechanical stimuli (Gerke and Plenderleith, 2001; Vulchanova et al., 2001). Previous studies indicated that human small- and medium-diameter TRG neurons co-express GDNF and GFRα-1 (Quartu et al., 1999, 2006).
Glial cell line-derived neurotrophic factor (GDNF) plays an important role in adult sensory neuron function. However, the acute effects of GDNF on primary sensory neuron excitability remain to be elucidated. The aim of the present study was to investigate whether GDNF acutely modulates the excitability of adult rat trigeminal ganglion (TRG) neurons that innervate the facial skin by using perforated-patch clamping, retrograde-labeling and immunohistochemistry techniques. Fluorogold (FG) retrograde labeling was used to identify the TRG neurons innervating the facial skin. The FG-labeled small- and medium-diameter GDNF immunoreactive TRG neurons, and most of these neurons also expressed the GDNF family receptor α-1 (GFRα-1). In whole-cell voltage-clamp mode, GDNF application significantly inhibited voltage-gated K⁺ transient (I_A) and sustained (I_K) currents in most dissociated FG-labeled small-diameter TRG neurons. This effect was concentration-dependent and was abolished by co-application of the protein tyrosine kinase inhibitor, K252b. Under current-clamp conditions, the repetitive firing during a depolarizing pulse were significantly increased by GDNF application. GDNF application also increased the duration of the repolarization phase and decreased the duration of the depolarization phase of the action potential, and these characteristic effects were also abolished by co-application of K252b. These results suggest that acute application of GDNF enhances the neuronal excitability of adult rat small-diameter TRG neurons innervating the facial skin, via activation of GDNF-induced intracellular signaling pathway. We therefore conclude that a local release of GDNF from TRG neuronal soma and/or nerve terminals may regulate normal sensory function, including nociception.
Reg-2 expression in dorsal root ganglion neurons after adjuvant-induced monoarthritis
2008, Neuroscience
Citation Excerpt :
Although cytokines are thought to play an important role in inflammation (Marchand et al., 2005), many of their effects on DRG neurons appear to be indirect and mediated by NGF (Woolf et al., 1997). It is clear that many IB4 neurons are nociceptors (Gerke and Plenderleith, 2001) but their exact role is unclear, and studies that have compared the responses properties of IB4-positive and IB4-negative neurons have identified only minor differences (Stucky and Lewin, 1999; Petruska et al., 2000; Dirajlal et al., 2003; Liu et al., 2004; Breese et al., 2005). Recently, however, a role for IB4 cells in inflammation has been proposed based on data showing that TRPV1 expression increases in IB4-positive cells (Amaya et al., 2004; Breese et al., 2005) as well as in IB4-negative (trkA immunoreactive) cells (Amaya et al., 2004) during inflammation.
Reg-2 is a secreted protein that is expressed de novo in motoneurons, sympathetic neurons, and dorsal root ganglion (DRG) neurons after nerve injury and which can act as a Schwann cell mitogen. We now show that Reg-2 is also upregulated by DRG neurons in inflammation with a very unusual expression pattern. In a rat model of monoarthritis, Reg-2 immunoreactivity was detected in DRG neurons at 1 day, peaked at 3 days (in 11.6% of DRG neurons), and was still present at 10 days (in 5%). Expression was almost exclusively in the population of DRG neurons that expresses the purinoceptor P2X₃ and binding sites for the lectin Griffonia simplicifolia IB4, and which is known to respond to glial cell line–derived neurotrophic factor (GDNF). Immunoreactivity was present in DRG cell bodies and central terminals in the dorsal horn of the spinal cord. In contrast, very little expression was seen in the nerve growth factor (NGF) responsive and substance P expressing population. However intrathecal delivery of GDNF did not induce Reg-2 expression, but leukemia inhibitory factor (LIF) had a dramatic effect, inducing Reg-2 immunoreactivity in 39% of DRG neurons and 62% of P2X₃ cells.
Changes in inflammation have previously been observed predominantly in the neuropeptide expressing, NGF responsive, DRG neurons. Our results show that changes also take place in the IB4 population, possibly driven by members of the LIF family of neuropoietic cytokines. In addition, the presence of Reg-2 in central axon terminals implicates Reg-2 as a possible modulator of second order dorsal horn cells.

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Brain Research

Abstract

Section snippets

Acknowledgements

References (11)

An α-d-galactosyl-binding lectin from Bandeiraea simplicifolia seeds

J. Biol. Chem.

A key to classification of cutaneous mechanoreceptors

J. Invest. Dermatol.

Selective labelling of primary sensory afferent terminals in lamina II of the dorsal horn by injection of Bandeiraea simplicifolia isolectin B4 into peripheral nerves

Neuroscience

The plant lectin Bandeiraea simplicifolia I-B₄ identifies a subpopulation of small diameter primary sensory neurones which innervate the skin in the rat

Neurosci. Lett.

Evidence for glycoconjugate in nociceptive primary sensory neurones and its origin from the Golgi complex

Brain Res.

Cited by (53)

Expression of NPR-B in neurons of the dorsal root ganglia of the rat

Specific functioning of Cav3.2 T-type calcium and TRPV1 channels under different types of STZ-diabetic neuropathy

GRK2 in sensory neurons regulates epinephrine-induced signalling and duration of mechanical hyperalgesia

Chloride transporters in presynaptic inhibition, pain and neurogenic inflammation

Glial cell line-derived neurotrophic factor acutely modulates the excitability of rat small-diameter trigeminal ganglion neurons innervating facial skin

Reg-2 expression in dorsal root ganglion neurons after adjuvant-induced monoarthritis

Short communicationBinding sites for the plant lectin Bandeiraea simplicifolia I-isolectin B4 are expressed by nociceptive primary sensory neurones

Abstract

Section snippets

Acknowledgements

J. Biol. Chem.

J. Invest. Dermatol.

Neuroscience

Neurosci. Lett.

Brain Res.

Short communication
Binding sites for the plant lectin Bandeiraea simplicifolia I-isolectin B₄ are expressed by nociceptive primary sensory neurones