Neuropeptides and ATP signaling in the trigeminal ganglion

Abstract

Peripheral nociceptive stimuli from orofacial structures are largely transmitted by the trigeminal nerve. According to the peripheral noxious stimuli, neurons in the trigeminal ganglion (TG) produce neuropeptides such as substance P, and calcitonin-gene-related peptide, etc. Beside the production of neuropeptides, there exists unique non-synaptic interaction system between maxillary and mandibular neurons in the TG. Neurons in the TG are surrounded by satellite glial cells (SGCs), which initially receive the signal from TG neurons. These activated SGCs secrete a transmitter to activate adjacent SGCs or TG neurons, thereby amplifying the signal, for example, from mandibular neurons to maxillary neurons in the TG. Similar to the dorsal root ganglion, in the TG, microglia/macrophage-like cells (MLCs) are activated by uptake of a transmitter from TG neurons or SGCs. This communication between neurons, SGCs, and MLCs results in responses such as ectopic pain, hyperesthesia, or allodynia. The focus of this review is the cooperative interaction of the maxillary and mandibular nerves in the TG by neuropeptides, and adenosine 3'-phosphate (ATP) signaling from neurons to SGCs and MLCs. Stimulated neurons either secrete ATP by means of vesicular nucleotide transporters, or secrete neuropeptides from the neuronal cell body to mediate signal transmission.

Keywords: ATP; ATP, adenosine 3′-phosphate; CGRP, calcitonin-gene-related peptide; DRG, dorsal root ganglion; MLC, microglia/macrophage-like cell; Neuron; Neuropeptides; PACAP, pituitary adenylate-cyclase-activating polypeptide receptor type 1; SGC, satellite glial cell; SP, substance P; Satellite glial cell; TG, trigeminal ganglion; Trigeminal ganglion; VIP, vasoactive intestinal peptide; VNUT, vesicular nucleotide transporter.

Figure 1

The proportion of SP-immunoreactive (IR) neurons per PGP-9.5-IR neuron (all neuron) in maxillary (A) and mandibular nerve region (B) in the TG at 3 h to 21 days after the maxillary first molar extraction. Control proportion indicated as Cont. Max (maxillary nerve region) and Cont. Md (mandibular nerve region) and extracted proportion indicated as Ext Max and Ext Md. Mean ± SD. Significant differences from control value at each time point (*p < 0.05 and **p < 0.01, tested by one-way ANOVA).

Figure 2

VNUT distribution in neurons and SGCs in the TG after rat molar extraction. (A–C)Double immunofluorescence staining using antibodies against VNUT (ATP transporter) and Activating Transcription Factor 3 (ATF3: a marker damaged neuron). VNUT-immunoreactive (IR) vesicles localize even in non-damaged TG neuron (A). (B, C) After 1 and 6 h after upper first molar extraction, the nuclei of damaged neurons were immunopositive for ATF3 (arrows) and the number of VNUT-IR vesicles in the cytoplasm of ATF3-immunopositive neurons increased in time-dependent manner. (D, E) Double immunofluorescence staining using antibodies against VNUT (ATP transporter) and glucose synthase (GS: a marker of SGCs). At 24 h after tooth extraction, few VNUT-IR vesicles exhibited in GS-immunopositive SGCs, however, at 48 h after extraction some VNUT-IR vesicles (arrowheads) distributed in SGCs. Bars = 10 μm.

Figure 3

Schematic diagram of ATP mediated neuron-SGCs-MLCs signaling in the TG. Once nociceptive signal reach TG neuron, the formation of the ATP containing vesicle increases by the cooperation of VNUT and V-ATPase. After the activation of TG neuron, the signal then reaches SGCs, and SGCs also produce ATP containing vesicles by the action of VNUT. Vesicles containing ATP in TG neurons and SGCs moved periphery and release ATP to extracellular space. Extracellular ATP binds ATP receptor (P2X₃, P2X₄, etc.) on adjacent SGCs, MLCs, or TG neurons. Released ATP would activate SGCs or MLCs and induce to secrete neurotrophic factors such as BDGF or NGF.

Figure 4

Schematic diagram of the cooperative interactions of the maxillary and mandibular nerves in the TG, accompanied with the neuronal signalling via ATP to SGCs and MLCs. Stimulated maxillary neurons shows positive for ATF3 (GFAP: glial fibrillary acidic protein, a marker of activated glial cells) and the nearby SGCs become GFAP positive (a maker of activated glial cell). Damaged maxillary neurons secrete ATP or neuropeptides from the neuronal cell body. Secreted ATP or unknown factors would induce the activation of MLCs, and the activated MLCs would secrete some neurotrophic factors such as brain-derived neurotrophic factor (BDNF). BDNF stimulates ATF3 negative maxillary and mandibular neurons surrounded by GFAP positive SGCs.