The ATP-mediated fast current of rat dorsal root ganglion neurons is a novel effector for GABAB receptor activation

doi:10.1016/S0304-3940(02)01369-1

Neuroscience Letters

Volume 338, Issue 3, 6 March 2003, Pages 181-184

https://doi.org/10.1016/S0304-3940(02)01369-1 Get rights and content

Abstract

Because γ-aminobutyric acid_B (GABA_B) agonists produce strong antinociception, the present study analyzed if GABA_B receptors might operate through depression of P2X₃ receptors responsible for fast adenosine triphosphate (ATP) currents involved in transmitting pain. On rat dorsal root ganglion (DRG) nociceptive neurons, inward currents induced by ATP were inhibited after 2 s or 60 s GABA application and unaffected after 10 s application. SKF-97541 or baclofen, potent GABA_B agonists, mimicked only the late inhibition of ATP currents. The effect of SKF-97541 or GABA was observed even after their transient application prior to ATP. The GABA_B antagonist CGP-52432 blocked the action of SKF-97541, suggesting a GABA_B receptor-mediated mechanism (the GABA_A antagonist picrotoxin was ineffective). It is suggested that, on nociceptive DRG neurons, GABA produced slow inhibition of P2X₃ receptors via metabotropic GABA_B receptors.

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Acknowledgements

This work was supported by grants from MIUR, INFM, INTAS and Fondo di Ricerca Regione FVG. We thank Dr Massimo Righi for his support with cell cultures.

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Neuropathic pain (NP) develops because of damage to the peripheral or central nervous system. It results in the hyperalgesia and allodynia. In the recent years, various researchers have studied the involvement of neuro-immune system in causing persistence of pain. The absence of synaptic contacts in the sensory ganglion makes them distinctive in terms of pain related signalling. In sensory ganglia, the neurotransmitters or the other modulators such as inflammatory substances produced by the ganglion cells, because of an injury, are responsible for the cross-excitation between neurons and neuron-glial interaction, thus affecting chemical transmission. This chemical transmission is considered mainly responsible for the chronicity and the persistent nature of neuropathic pain. This review examines the pain signalling due to neurotransmitter or cytokine release within the sensory ganglia. The specific areas focused on include: 1) the role of neurotransmitters released from the somata of sensory neurons in pain, 2) neuron-glia interaction and 3) role of cytokines in neuromodulation and pain.
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The function of membrane receptor and channel is controlled by intracellular molecules that regulate their stability, phosphorylation and membrane segregation. In certain conditions, co-expression of receptors of different nature in the same membrane domain favour their functional transactivation (Sokolova et al., 2003; Toulmé et al., 2007). Considering that high levels of extracellular ATP are associated to tissue acidification in many pathological conditions, such as inflammation, ischemia or cancer, it is not surprising that these signals might converge into coordinated activation of both purinergic and acid-sensing receptors (Immke and McCleskey, 2001; Hanaka et al., 2018; Stephan et al., 2018).
Peripheral stimuli are transduced by specific receptors expressed by sensory neurons and are further processed in the dorsal horn of spinal cord before to be transmitted to the brain. While relative few receptor subtypes mediate the initial depolarisation of sensory neurons, an impressive number of molecules and ion channels integrate these inputs into coded signals. Soluble mediators and ambient conditions further shape these processes, potentially triggering peripheral and central sensitisation, or sensory downregulation. Extracellular ATP is a major signaling molecule that acts via purinergic receptors and is a powerful modulator of cell communication as well as a neurotransmitter at peripheral/central synapses. In particular, ATP-mediated signals are transduced by P2X3 receptors expressed mainly by peripheral sensory neurons. Recent evidence suggests that P2X3 receptor function not only induces neuron depolarisation and firing with consequent neurotransmitter release, but it also triggers intracellular molecular changes that amplify purinergic signaling with important consequences.
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It has been reported that GABA is released from TRG neurons by increasing extracellular K+ concentrations, indicating that GABA acts as a non-synaptically released diffusible neurotransmitter that may modulate somatic inhibition of TRG neurons via both GABAA and GABAB receptors (Hayasaki et al., 2006, 2012). Sokolova et al. (2001, 2003) demonstrated that ATP was coreleased with GABA and ATP-induced inward currents in nociceptive DRG neurons, and that this effect was modulated by GABA. In fact, we have recently reported that the ATP-activated excitability of small-diameter TRG neurons is inhibited by activation of GABAB receptors, suggesting that activation of GABAB receptors on small-diameter TRG neuronal cell bodies contributes to modification of trigeminal nociceptive transmission (Takeda et al., 2013).
In a previous study, we demonstrated that inflammation suppressed inward rectifying K⁺ (Kir) currents in satellite glial cells (SGCs) from the trigeminal ganglia (TRGs) and that this impairment of glial potassium homeostasis in the trigeminal ganglion (TRG) contributed to trigeminal pain. The aim of the present study was to investigate whether activation of GABA_B receptors modulates the Kir current in SGCs using in vivo patch-clamp and immunohistochemical techniques. Immunohistochemically, we found that immunoreactivity for glial-specific Kir channel subunit Kir4.1 and the GABA_B receptor was co-expressed in SGCs from the TRGs. In vivo whole-cell recordings were made using SGCs from the TRGs of urethane-anesthetized rats. Application of baclofen, a GABA_B receptor agonist, significantly increased the mean peak amplitude of Kir currents in a concentration-dependent and reversible manner. Baclofen-induced potentiation of the Kir current was abolished by co-application of 3-amino-2-(4-chlorophenyl)-2-hydroxyprophylsulfonic acid (saclofen). In addition, baclofen significantly potentiated the density of the Ba²⁺-sensitive Kir current, and resulted in hyperpolarization of the mean membrane potential. These results suggest that activation of GABA_B receptors potentiates the Kir current in SGCs and that GABA released from the TRG neuronal soma could contribute to buffering of extracellular K⁺ concentrations following excitation of TRG neurons during the processing of sensory information, including the transmission of noxious stimuli.
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This idea is further supported by our observation that mean resting membrane potential was significantly hyperpolarized after baclofen application due to the activation of GABAB receptor induced outward currents in this study. Alternatively, in agreement with an earlier report from Sokolova et al. (2003), we observed the slow (long-lasting) inhibition of ATP-induced current by GABAB receptors in this study. It is known that activation of GABAB receptor inhibits Ca2+ channels and fast occlusion of ATP-induced currents is meditated by Ca2+ influx from voltage-gated Ca2+ channels (Dorphin and Scott, 1987; MacDermott et al., 1999; Sokolova et al., 2003).
The aim of the present study was to investigate whether a GABA_B receptor agonist could modulate ATP-activated neuronal excitability of nociceptive TRG neurons using perforated whole-cell patch-clamp and immunohistochemical techniques. Immunohistochemical analysis revealed that 86% of P₂X₃ receptor-immunoreactive, small-diameter TRG neurons co-expressed GABA_B receptor. Under voltage-clamp conditions (V_h = −60 mV), application of ATP activated the inward current in acutely isolated rat TRG neurons in a dose-dependent manner (10–50 μM) and this current could be blocked by pyridoxal-phosphate-6-azophenyl-27,47-disulfonic acid (PPADS) (10 μM), a selective P₂ purinoreceptor antagonist. The peak amplitude of ATP-activated currents was significantly inhibited after application of GABA_B receptor agonist, baclofen (10–50 μM), in a concentration-dependent and reversible manner. The baclofen-induced inhibition of ATP-activated current was abolished by co-application of 3-amino-2 (4-chlorophenyl)-2hydroxypropysufonic acid) saclofen, a GABA_B receptor antagonist (50 μM). Under current-clamp conditions, application of 20 μM ATP significantly depolarized the membrane potential resulting in increased mean action potential frequencies, and these ATP-induced effects were significantly inhibited by baclofen and these effects were antagonized by co-application of saclofen. Together, the results suggested that GABA_B receptor activation could inhibit the ATP-induced excitability of small-diameter TRG neurons activated through the P₂X₃ receptor. Thus, the interaction between P₂X₃ and GABA_B receptors of small-diameter TRG neuronal cell bodies is a potential therapeutic target for the treatment of trigeminal nociception.
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These results suggest that, contrary to the classical view, neuronal cell bodies in sensory ganglia might have an important function in neuronal signaling transduction, which might be mediated by the GABAergic system. Considering the anatomical and functional similarity of the TG and the DRG, it might be expected that both GABAA and GABAB receptors are expressed in primary sensory neurons and function in a similar manner in both types of ganglia (Yang et al., 2001; Sokolova et al., 2003; Rustioni, 2005). Actually, the GABA agonist baclofen has been approved for the treatment of spasticity and many types of neuropathic pain including trigeminal neuralgia (Fromm, 1994).
It is well known that Gamma-aminobutyric acid (GABA) plays an important role in signal transduction in the central nervous system. However, the function of GABA in the peripheral nervous system, including sensory ganglions, is still unclear. In this study we have characterized the expression, cellular distribution, and function of GABA_B receptor subunits, and the recently discovered GABA_B auxiliary subunits, K⁺ channel tetramerization domain-containing (KCTD) proteins, in rat trigeminal ganglion (TG) neuronal cells, which are devoid of synapses. We found heterogeneous expression of both GABA_B1 and GABA_B2 subunits, and a near-plasma membrane localization of KCTD12. In addition, we found that GABA_B2 subunits correlated with KCTD16. Whole-cell current-clamp recordings showed that responses to the GABA_B receptor agonist, baclofen, were variable and both increases and decreases in excitability were observed. This correlated with observed differences in voltage-dependent K⁺ current responses to baclofen in voltage-clamped TG neuronal cells. The functional diversity of the GABA_Bergic regulation on the excitability of the TG neuronal cell bodies could be due to the heterogenous expression of KCTD proteins, and subsequent regulation of plasma membrane K⁺ channels. Taken together with our previous demonstration of a local GABA_A receptor-mediated system in rat TG, we provide an updated GABAergic model in the rat TG that incorporates both GABA_A- and GABA_B-receptor systems.
Analgesic effect of electroacupuncture on chronic neuropathic pain mediated by P2X <inf>3</inf> receptors in rat dorsal root ganglion neurons
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Adenosine 5′-triphosphate disodium (ATP) gated P2X receptors, especially the subtype P2X₃, play a key role in transmission of pain signals in neuropathic pain, ATP has been documented to play a significant role in the progression of pain signals, suggesting that control of these pathways through electroacupuncture (EA) is potentially an effective treatment for chronic neuropathic pain. EA has been accepted to effectively manage chronic pain by applying the stimulating current to acupoints through acupuncture needles. To determine the significance of EA on neuropathic pain mediated by P2X₃ receptors in the dorsal root ganglion (DRG) neurons, mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded, and the expression of P2X₃ receptors in the DRG neurons was assessed by immunohistochemistry (IHC) and in situ hybridization (ISH). In addition, the currents which were evoked in DRG neurons isolated from rats following chronic constriction injury (CCI) by the P2X₃ receptors agonists i.e. ATP and α,β-methylen-ATP (α,β-meATP) were examined through the experimental use of whole cell patch clamp recording. The present study demonstrates that EA treatment can increase the MWT and TWL values and decrease the expression of P2X₃ receptors in DRG neurons in CCI rats. Simultaneously, EA treatment attenuates the ATP and α,β-meATP evoked currents. EA may be expected to induce an apparent induce analgesic effect by decreasing expression and inhibiting P2X₃ receptors in DRG neurons of CCI rats. There is a similar effect on analgesic effect between rats with contralateral EA and those with ipsilateral EA.

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The ATP-mediated fast current of rat dorsal root ganglion neurons is a novel effector for GABAB receptor activation

Abstract

Section snippets

Acknowledgements

Trends Pharmacol. Sci.

Mol. Cell. Neurosci.

Neuropharmacology

Eur. J. Pharmacol.

Prog. Neurobiol.

Electrophysiological actions of GABAB agonists and antagonists in rat dorso-lateral septal neurones in vitro

Br. J. Pharmacol.

γ-Aminobutyric acidB receptors: first of the functional metabotropic heterodimers

J. Pharmacol. Exp. Ther.

Homer: a protein that selectively binds metabotropic glutamate receptors

Nature

P2X receptor-mediated ionic currents in dorsal root ganglion neurons

J. Neurophysiol.

Inhibition of the interaction of G protein Go with calcium channels by the calcium channel beta-subunit in rat neurones

J. Physiol. (London)

Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice

Nature

A memory for extracellular Ca2+ by speeding recovery of P2X receptors from desensitization

J. Neurosci.

The ATP-mediated fast current of rat dorsal root ganglion neurons is a novel effector for GABA_B receptor activation

Electrophysiological actions of GABA_B agonists and antagonists in rat dorso-lateral septal neurones in vitro

γ-Aminobutyric acid_B receptors: first of the functional metabotropic heterodimers

Inhibition of the interaction of G protein G_o with calcium channels by the calcium channel beta-subunit in rat neurones

Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X₃-deficient mice

A memory for extracellular Ca²⁺ by speeding recovery of P2X receptors from desensitization