Glial cell line-derived neurotrophic factor acutely modulates the excitability of rat small-diameter trigeminal ganglion neurons innervating facial skin
Introduction
Glial cell line-derived neurotrophic factor (GDNF) is known to have neurotrophic actions on different types of neurons in the central and peripheral nervous system, including primary afferent sensory neurons (Lapchak et al., 1996, Unsicker, 1996, Bennett et al., 1998, Bennett et al., 2000, Prince et al., 2005). The GDNF family ligands signal through a receptor complex consisting of the common transmembrane tyrosine kinase receptor Ret, and one of four ligand binding receptor components, called GDNF family receptors (GFRα-1 to -4), with GFRα-1 the preferred receptor for GDNF (Airaksinen and Saarma, 2002). During development, the survival of most sensory neurons is dependent on nerve growth factor (NGF), and these small- to medium-sized neurons express the NGF receptor trkA (Crowley et al., 1994, Koltzenburg, 1999; Quartu et al., 1996). However, during the late embryonic and postnatal period, some small- to medium-sized neurons that are initially trkA positive, switch dependency to GDNF and express GFRα-1 (Silverman and Kruger, 1988, Molliver et al., 1997, Bennett et al., 1998), suggesting that GDNF plays an important role in mature sensory neuron function. There is evidence that NGF, GDNF and BDNF (Brain-derived neurotorophic factor) differentially alter trigeminal ganglion (TRG) neuron survival, neurochemical properties and transient receptor potential vanilloid receptor type 1 (TRPV1)-mediated neuropeptide release (Prince et al., 2005). In fact, GFRα-1 is expressed by small-diameter dorsal root ganglion (DRG) neurons, particularly those which bind isolectin B4 (IB4), which is believed to play a role in nociception (Silverman and Kruger, 1988, Akkina et al., 2001, Bennett et al., 1998, Molliver et al., 1997). In addition, the axons of these neurons project onto the superficial layer of spinal dorsal horn (Holstege et al., 1998, Jongen et al., 1999, Kawamoto et al., 2000). Taken together, these findings suggest that GDNF and GFRα-1 expression by small-diameter sensory neurons is related to nociception.
There is increasing evidence of cross-excitation in the sensory ganglia, and recent studies have demonstrated that non-synaptically released diffusible chemical messengers, such as ATP, substance P (SP) and calcitonin gene-related peptide (CGRP), may modify the somatic excitability of neurons in the sensory ganglia (Amir and Devor, 1996, Amir and Devor, 2000, Takeda et al., 2005a, Takeda et al., 2005b, Zhang et al., 2007, Jing et al., 2008, Durham, 2008). For example, the release of SP in TRG neurons increases predominantly after peripheral inflammation, indicating that local paracrine mechanisms in the sensory ganglia contribute to the development of inflammation-induced sensory abnormalities (Matsuka et al., 2001, Takeda et al., 2005a, Takeda et al., 2005b). Quartu et al. (1996) have reported that human GDNF positive TRG neurons also expressed SP/CGRP immunoreactivity at all ages examined and satellite glia cell occasionally expressed GDNF. Recent studies demonstrated that small- and medium-diameter human TRG neurons also express GDNF and the GFRα-1 receptor (Quartu et al., 1999, Quartu et al., 2006), suggesting that local paracrine and/or autocrine mechanisms of GDNF within the trigeminal ganglia may contribute to modulation of the nociceptive TRG neuronal excitability.
Two different modes of action (long- and short-term effects) have been reported to explain the excitatory effects of GDNF. Long-term treatment with GDNF modulates synapses made by the midbrain dopaminergic neurons (Lin et al., 1993, Brizard et al., 2006). Amperometric recording demonstrates that treatment with GDNF can enhance quantal release of synaptic neurotransmitters in cultured dopaminergic neurons (Pothos et al., 1998). Also, GDNF up-regulates tetrodotoxin-resistant (TTX-R) sodium channels in small-diameter DRG neurons after their axons are injured (Cummins et al., 2000). In addition to those long-term effects, it has also been reported that acute application of GDNF to midbrain dopaminergic neurons suppresses A-type potassium channels and potentiates neuronal excitability through a mechanism that involves activation of mitogen activated protein (MAP) kinase (Yang et al., 2001). Wang et al. (2003) reported acute potentiation of voltage-gated Ca2+ channels and excitatory synaptic transmission in dopaminergic neurons by GDNF application. Therefore, these data suggest that GDNF may acutely modulate voltage-gated ion channels in normal neuronal excitability rather than the long-term regulation of survival.
Voltage-gated potassium (K+) channels are important physiological regulators of membrane excitability in sensory ganglia (Ficker and Heinemann, 1992, Peace and Duchen, 1994, Lawson, 2006, Dang et al., 2004, Takeda et al., 2006). DRG and TRG neurons express three distinct classes of K+ currents in varying quantities: dominant-sustained (K-current; IK), fast-inactivating transient (A-current; IA, corresponding to A-type K+ current) and slow-inactivating transient (D-current; ID) currents (Evervill et al., 1999; Takeda et al., 2004, Yoshida and Matsumoto, 2005). Our laboratory previously reported that in TTX-R small-diameter TRG neurons, a reduction in IA current density contributed to the increased excitability seen after temporomandibular (TMJ) inflammation (Takeda et al., 2006). More recently, it was also documented that BDNF enhances DRG neuron excitability via the suppression of IK (Zhang et al., 2008). Taken together, these results led us to hypothesize that acute application of GDNF may modify nociceptive TRG neuronal excitability. This idea was further supported by the evidence that, in a transgenic mouse that over-expressed GDNF in the skin, IB4 positive/GDNF responsive DRG neurons exhibited significantly lower thresholds to mechanical stimulation than wild-type neurons (hyperalgesia) (Albers et al., 2006).
Therefore, the aim of the present study was to test the hypothesis that acute application of GDNF modulates the neuronal excitability of TRG neurons innervating the facial skin, by using perforated patch-clamp combined with retrograde-labeling and immunohistochemistry.
Section snippets
Material and methods
The experiments were approved by the Animal Use and Care Committee of Nippon Dental University and were consistent with the ethical guidelines of the International Association for the Study of Pain (Zimmermann, 1983). Every effort was made to minimize the number of animals used and their suffering.
Immunoreactivity of GDNF and GFRα-1 in the TRG neurons innervating facial skin
According to our previous immunohistochemical examinations (Takeda et al., 2007a, Takeda et al., 2007b), TRG cell bodies were classified according to size as small (<30 μm), medium (30–39 μm) or large (>40 μm). As shown in Fig. 1A, small- and medium-diameter TRG neurons were immunoreactive for GDNF as described previously (Quartu et al., 1999). Most of these neurons (88%) were also immunoreactive for the GFRα-1 (Fig. 1B and C). The size frequency distribution of GDNF and GFRα-1 immunoreactive TRG
Discussion
The present study provides evidence that acute application of GDNF enhances the neuronal excitability of adult rat small-diameter TRG neurons, which innervate the facial skin in the absence of neuropathic and inflammatory conditions. This potentiation of small-diameter TRG neuronal excitability is mediated by inhibition of voltage-gated outward K+ channels via the activation of GDNF-induced intracellular signaling pathway. These alternations in cellular excitability may account for enhanced
Acknowledgments
This study was supported by a Grant-in-Aid for Scientific Research from the Japanease Society for Promotion of Science (No. 21592377).
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2013, Brain, Behavior, and ImmunityCitation Excerpt :Taken together, our result indicate that GDNF and its functional receptors, which are located on the soma of facial skin-innervating TRG neurons, may contribute to transganglionic trigeminal nociceptive transmission via paracrine and/or autocrine mechanisms, as well as via nerve terminals. Several types of non-synaptically released chemical mediators, such as ATP, SP, CGRP, cytokines and growth factors, have been shown to modify the somatic excitability of neurons in the sensory ganglia (Amir and Devor, 1996, 2000; Takeda et al., 2005a, 2005b, 2009, 2010; Zhang et al., 2007; Jing et al., 2008; Durham, 2008; Balkowiec-Iskra et al., 2011). SP and interleukin-1β are released within TRGs after peripheral inflammation and contribute to the development of inflammation-induced sensory abnormalities, involving inflammatory allodynia and hyperalgesia (Matsuka et al., 2001; Takeda et al., 2005a, 2005b, 2009, 2010).
GDNF induces mechanical hyperalgesia in muscle by reducing I<inf>BK</inf> in isolectin B4-positive nociceptors
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The neuronal potassium current I<inf>A</inf> is a potential target for pain during chronic inflammation
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