Fig. 1. Schematic showing the neurotransmitters, receptors and ion channels that are modulated and up-regulated by NGF binding to TrkA-positive primary afferent sensory nerve fibers. Tropomyosin-related kinase A receptor (TrkA)-positive primary afferent nerve fibers have their cell body in the dorsal root ganglia (DRG) and transmit sensory information from the periphery to the spinal cord and brain. During inflammation, injury, or certain diseases, inflammatory, immune, or Schwann cells release nerve growth factor (NGF) that binds to TrkA, which in turns directly activates and/or sensitizes nociceptors (A ). NGF and its cognate receptor TrkA are transported in a retrograde direction to the DRG, resulting in increased synthesis of neuropeptides (e.g. , substance P [SP], brain-derived neurotrophic factor [BDNF]), receptors, ion channels, and anterograde transport of certain neurotransmitters, receptors, and ion channels from the DRG to the periphery tissue and spinal cord. NGF is released during inflammatory injury, principally from mast cells but also from other recruited cells (B ). Binding of NGF to TrkA on mast cells causes release of inflammatory mediators, such as histamine, serotonin (5HT), and protons (H+), as well as NGF. Binding of NGF to TrkA on the peptidergic (TrkA-positive) fiber terminal activates intracellular signaling pathways (represented by arrows ), which results in either increased expression (bold ) or modulation (↑ or ↓) at the membrane surface of a number of receptors, including bradykinin (BK) receptors (B2R); ion channels, including transient receptor potential vanilloid 1 (TRPV1); acid-sensing ion channels (ASIC) 2/3; voltage-gated sodium (Nav) or calcium (Cav) ion channels; delayed rectifier potassium (K+) currents; and putative mechanotransducers. These rapid changes (taking from minutes to hours) in the afferent terminal modify the sensory fiber's response to sensory stimuli and the propagation of sensory impulses to the dorsal horn. CGRP = calcitonin gene-related peptide.