Nerveimmune Interactions And Peripheral Sensitization

The previous sections described how inflammatory mediators modulate the function of sensory neurons. However, neurons also affect immune cells, many of which express receptors for neuropeptides such as substance-P, calcitonin-gene-related peptide (CGRP), or

Figure 8 Presynaptic mechanisms of altered synaptic transmission in nociceptive signaling. Inflammation increases calcium currents, which will enhance transmitter release. This can be associated with changes in transmitter expression. Silent synapses may become active or sprouting of central nerve terminals may lead to the formation of new synapses.

Figure 8 Presynaptic mechanisms of altered synaptic transmission in nociceptive signaling. Inflammation increases calcium currents, which will enhance transmitter release. This can be associated with changes in transmitter expression. Silent synapses may become active or sprouting of central nerve terminals may lead to the formation of new synapses.

somatostatin (131-134). Therefore, release of these peptides from nerve terminals can attract and/or activate immune cells, thereby contributing to the inflammatory response (neurogenic inflammation) (135,136). A family of G-protein-coupled receptors, the protease-activated receptors (PAR), demonstrates the potential importance of this cross talk between sensory neurons and immune cells. In addition to inflammatory mediators, immune cells release proteases such as cathepsin G or tryptase into the interstitial space. These enzymes cleave the N terminal of PAR, thereby releasing a small peptide that activates the G-protein. PAR-2 receptors are expressed on extrinsic and intrinsic visceral sensory neurons (137,138). Activation of these receptors triggers an increase in intracellular calcium and release of neurotransmitters, which interact with mast cells and other immune cells, leading to protease release and further pro-teolytic activation of PAR-2 receptors. Considering the high concentration of proteases within the pancreas, this pathway may play an especially important role in pain development during pancreatic diseases (139). However, PAR-2 may play a role in other areas because it can be activated by mast cells, which are found in close proximity to nerves and release tryptase (140,141). Consistent with such a more general role of PAR-2 activation, the PAR-2-activating peptide enhanced responses to colorectal distension in rats (142).

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