Synaptic Transmission

When the action potential invades the presynaptic terminal, VSCC open and allow calcium influx, which triggers the fusion of transmitter vesicles with the cell membrane and release of neurotransmitter. The exocytic transmitter release is steeply dependent on the intracellular calcium concentration (111). Therefore, increases in calcium currents due to changes in channel properties or expression during inflammation may enhance transmitter release. In addition, proteins regulating the fusion of vesicles with the presynaptic membrane are subject to modulation and can increase or decrease transmitter release. While this presynaptic facilitation is an important mechanism for memory formation and learning, its relevance in the development of hyperalgesia remains unknown (112).

Glutamate is the main transmitter within the spinal cord and—in the case of the vagus— the nucleus of the solitary tract (113,114). In many nerve terminals, glutamate coexists with neuropeptides, which are stored in larger vesicles that appear dense in electron microscopic images (115). Substance-P plays a unique role in this context because it is primarily found in unmyelinated C fibers. Chemical ablation of these nerve fibers with the neurotoxin capsaicin blunts responses to painful stimuli, pointing at an important role of substance-P-containing neurons in nociception (116,117). Consistent with this assumption, innocuous stimulation generally does not trigger substance-P release, while noxious stimuli or visceral inflammation cause the release of this transmitter (118). Conversely, substance-P antagonists or knockout mice deficient in substance-P or its receptor exhibit blunted responses to painful visceral stimulation (119-122). Inflammation rapidly activates the transcription of substance-P and other neurotransmitters in primary sensory neurons, which may affect synaptic transmission

Figure 7 Calcium currents in visceral inflammation. The left panel shows families of calcium currents triggered by stepwise depolarization between -100 mV (A) and -40 mV (b). The digital subtraction reveals a transient component activated by hyperpolarization (C). The current-voltage relationship demonstrates that calcium currents activate at more native potentials in nodose neurons obtained from animals with gastric ulcerations (D).

Figure 7 Calcium currents in visceral inflammation. The left panel shows families of calcium currents triggered by stepwise depolarization between -100 mV (A) and -40 mV (b). The digital subtraction reveals a transient component activated by hyperpolarization (C). The current-voltage relationship demonstrates that calcium currents activate at more native potentials in nodose neurons obtained from animals with gastric ulcerations (D).

(123-125). Combined with other changes such as enhanced neuron excitability and calcium influx into the presynaptic terminal, the altered transmitter expression may contribute to the increased activation of substance-P-receptors in the spinal cord (118,126). In addition, previously silent synapses can become active and sprouting of nerve terminals after injury or inflammation may establish new connections in the spinal cord (127-130). Many of these newly formed synapses convey information about innocuous stimuli onto neurons within regions involved in nociception (lamina I or II of the spinal cord), thus providing a potential mechanism for the development of allodynia (Fig. 8).

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