Capsaicin facilitates excitatory but not inhibitory synaptic transmission in substantia gelatinosa of the rat spinal cord

Yang, Kun; Kumamoto, Eiichi; Furue, Hidemasa; Yoshimura, Michihiro

doi:10.1016/s0304-3940(98)00730-7

Cited by 164 publications

(138 citation statements)

References 16 publications

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“…The proposed presynaptic function of mitochondria (Fig. 9F ) may also help to explain the previous observations by several groups that brief TRPV1 activation triggers long-lasting release of glutamate and prolonged synaptic activity in the spinal cord and brainstem slices (Ueda et al, 1993;Yang et al, 1998;Marinelli et al, 2002Marinelli et al, , 2003Nakatsuka et al, 2002).…”

Section: Trpv1 Mediates Presynaptic Casupporting

confidence: 60%

“…Indeed, TRPV1 colocalizes with the presynaptic protein synaptophysin, and TRPV1-positive axonal boutons containing synaptic vesicles have been observed by electron microscopy (Guo et al, 1999;Hwang et al, 2004). Moreover, stimulation of the central terminals of primary afferents with endovanilloids or capsaicin triggers the release of calcitonin gene-related peptide (CGRP) and substance P and induces glutamatergic synaptic transmission (Yang et al, 1998;Tognetto et al, 2001;Huang et al, 2002;Nakatsuka et al, 2002;Labrakakis and MacDermott, 2003). Although Ca 2ϩ dynamics at the sites of transmitter release are crucial for TRPV1-mediated responses, the mechanisms that shape presynaptic Ca 2ϩ signals in primary sensory neurons remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of Prolonged Presynaptic Ca²⁺Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons

Kim²,

2008

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Transient receptor potential vanilloid receptor 1 (TRPV1)-mediated release of neuroactive peptides and neurotransmitters from the peripheral and central terminals of primary sensory neurons can critically contribute to nociceptive processing at the periphery and in the CNS. However, the mechanisms that link TRPV1 activation with Ca 2ϩ signaling at the release sites and neurosecretion are poorly understood. Here we demonstrate that a brief stimulation of the receptor using either capsaicin or the endogenous TRPV1 agonist N-arachidonoyl-dopamine induces a prolonged elevation of presynaptic [Ca 2ϩ ] i and a concomitant enhancement of glutamate release at sensory synapses. Initiation of this response required Ca 2ϩ entry, primarily via TRPV1. The sustained phase of the response was independent of extracellular Ca 2ϩ and was prevented by inhibitors of mitochondrial Ca 2ϩ uptake and release mechanisms. Measurements using a mitochondria-targeted Ca 2ϩ indicator, mtPericam, revealed that TRPV1 activation elicits a long-lasting Ca 2ϩ elevation in presynaptic mitochondria. The concentration of TRPV1 agonist determined the duration of mitochondrial and cytosolic Ca 2ϩ signals in presynaptic boutons and, consequently, the period of enhanced glutamate release and action potential firing by postsynaptic neurons. These data suggest that mitochondria control vanilloid-induced neurotransmission by translating the strength of presynaptic TRPV1 stimulation into duration of the postsynaptic response.Key words: TRPV1; capsaicin; NADA; calcium; mitochondria; DRG neurons IntroductionThe transient receptor potential vanilloid receptor 1 (TRPV1) is a critical molecular detector of noxious signals in primary sensory neurons. A broad range of pain-producing stimuli either directly activate or modulate TRPV1. This includes noxious heat, protons, lipid-derived endovanilloids, and inflammatory mediators (Caterina and Julius, 2001;De Petrocellis and Di Marzo, 2005). Behavioral studies using TRPV1 knock-out mice or selective TRPV1 antagonists have indicated that the receptor is involved in the development of various chronic pain conditions, including those associated with cancer, arthritis, irritable bowel syndrome, and migraine (Caterina et al., 2000;Davis et al., 2000;Akerman et al., 2004;Ghilardi et al., 2005;Jones et al., 2005;Szabo et al., 2005). Accordingly, TRPV1 presents an attractive target for analgesics, and several TRPV1 antagonists are currently under preclinical investigation or clinical trials (Immke and Gavva, 2006;Szallasi et al., 2007).TRPV1 is a nonselective cation channel with a high Ca 2ϩ permeability, and robust Ca 2ϩ entry into the cell is a hallmark of receptor activation (Caterina et al., 1997). At the peripheral terminals of primary nociceptors, TRPV1-mediated Ca 2ϩ influx triggers the release of neuropeptides, which contributes to the development of neurogenic inflammation (Caterina and Julius, 2001). TRPV1 is also found in the central processes of primary afferent neurons (Guo et al., 1999;Hwang et al., 2004), and...

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Section: Trpv1 Mediates Presynaptic Casupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Mechanisms of Prolonged Presynaptic Ca²⁺Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons

Kim²,

2008

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“…VR1 activation typically increases excitability of neurons and synaptic terminals, and consequently enhances synaptic glutamate release. Activity at VR1 receptors is typically studied at the cellular level in the context of somatic or visceral sensory modulation (Tominaga et al, 1998;Yang et al, 1998;Zygmunt et al, 1999;Hwang et al, 2000;Bailey et al, 2002;Doyle et al, 2002;Evans et al, 2003;Jin et al, 2004a). Activation of VR1 can be achieved by increasing the temperature above 42°C or by lowering the pH below physiological levels (Tominaga et al, 1998;Premkumar and Ahern, 2000), conditions which cannot be met without disturbing normal brain activity.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the eventual decrease in evoked IPSC amplitude occurred concurrently with a VR1-mediated enhancement of mIPSC frequency. Analogous to VR1-mediated effects on EPSCs in substantia nigra or dorsal horn (Yang et al, 1998;Marinelli et al, 2003), the reduction in evoked IPSC amplitude may involve mechanisms resultant from sustained calcium influx or depolarization of afferent neurons or terminals. An inactivating, VR1-mediated inward current is observed in a subset of NTS neurons and could contribute to the eventual diminution of responses evoked after stimulating the NTS.…”

Section: Discussionmentioning

confidence: 99%

Vanilloid-Mediated Heterosynaptic Facilitation of Inhibitory Synaptic Input to Neurons of the Rat Dorsal Motor Nucleus of the Vagus

Derbenev

Monroe²,

Glatzer³

et al. 2006

J. Neurosci.

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Vanilloid type-1 receptors (VR1) are abundant in the dorsal vagal complex, where their function is mostly unknown. We examined the role of VR1 in regulating synaptic inputs to neurons of the dorsal motor nucleus of the vagus (DMV). Using patch-clamp recordings from DMV neurons in brainstem slices, capsaicin was found to increase action potential-independent inhibitory input onto DMV neurons. This rapid effect was mimicked by application of the endogenous cannabinoid, anandamide and blocked by VR1 antagonists. The VR1-mediated facilitation of synaptic inhibition was reduced by ionotropic and metabotropic glutamate receptor antagonists, suggesting an indirect, heterosynaptic enhancement of GABA release caused by a VR1-mediated increase in glutamate release from presynaptic terminals of excitatory neurons. Application of L-glutamate also increased GABA release. The paired-pulse ratio was increased for IPSCs evoked after electrical stimulation of the nucleus tractus solitarius, but the effect was slower than for the enhancement of spontaneous and miniature IPSCs. Capsaicin also increased the frequency of glutamatergic postsynaptic currents in a VR1-mediated manner. Results of these studies suggest that VR1-containing glutamatergic terminals contact DMV neurons. Activation of VR1 potently enhances glutamate release onto GABAergic terminals, facilitating GABA release. Endogenous cannabinoids can thereby rapidly enhance inhibitory input to DMV neurons via VR1-mediated presynaptic mechanisms.

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“…Capsaicin potently increases the frequency, but not the amplitude, of miniature EPSCs (mEPSCs) in a DRG-dorsal horn neuronal coculture system (Sikand and Premkumar, 2007), as well as in a spinal slice condition (Yang et al, 1998), suggesting that TRPV1-mediated neurotransmitter release from presynaptic terminals of nociceptive neurons contributes to nociceptive transmission. Despite these findings, however, the underlying mechanisms for the activation of central presynaptic TRPV1 under pathophysiological conditions remain unknown (Patapoutian et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Membrane-Delimited Coupling of TRPV1 and mGluR5 on Presynaptic Terminals of Nociceptive Neurons

Kim¹,

Park²,

Back³

et al. 2009

J. Neurosci.

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Transient receptor potential vanilloid subtype 1 (TRPV1) and metabotropic glutamate receptor 5 (mGluR5) located on peripheral sensory terminals have been shown to play critical roles in the transduction and modulation of pain sensation. To date, however, very little is known regarding the significance of functional expression of mGluR5 and TRPV1 on the central terminals of sensory neurons in the dorsal horn of the spinal cord. Here we show that TRPV1 on central presynaptic terminals is coupled to mGluR5 in a membranedelimited manner, thereby contributing to the modulation of nociceptive synaptic transmission in the substantia gelatinosa neurons of the spinal cord. Further, our results demonstrate that TRPV1 is involved in the pain behaviors induced by spinal mGluR5 activation, and diacylglycerol produced by the activation of mGluR5 mediates functional coupling of mGluR5 and TRPV1 on the presynaptic terminals. Thus, mGluR5-TRPV1 coupling on the central presynaptic terminals of nociceptive neurons may be an important mechanism underlying central sensitization under pathological pain conditions.

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Capsaicin facilitates excitatory but not inhibitory synaptic transmission in substantia gelatinosa of the rat spinal cord

Cited by 164 publications

References 16 publications

Mechanisms of Prolonged Presynaptic Ca²⁺Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons

Mechanisms of Prolonged Presynaptic Ca²⁺Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons

Vanilloid-Mediated Heterosynaptic Facilitation of Inhibitory Synaptic Input to Neurons of the Rat Dorsal Motor Nucleus of the Vagus

Membrane-Delimited Coupling of TRPV1 and mGluR5 on Presynaptic Terminals of Nociceptive Neurons

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Capsaicin facilitates excitatory but not inhibitory synaptic transmission in substantia gelatinosa of the rat spinal cord

Cited by 164 publications

References 16 publications

Mechanisms of Prolonged Presynaptic Ca2+Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons

Mechanisms of Prolonged Presynaptic Ca2+Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons

Vanilloid-Mediated Heterosynaptic Facilitation of Inhibitory Synaptic Input to Neurons of the Rat Dorsal Motor Nucleus of the Vagus

Membrane-Delimited Coupling of TRPV1 and mGluR5 on Presynaptic Terminals of Nociceptive Neurons

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Mechanisms of Prolonged Presynaptic Ca²⁺Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons

Mechanisms of Prolonged Presynaptic Ca²⁺Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons