FIGURE 8.

Contributions of tachykinins and neurokinin receptors to neurogenic inflammation and pain. 1: Noxious stimulation of peripheral tissues leads to the release or generation of multiple factors that derive from the circulation, immune cells, and epithelial tissues. These can include proteases (e.g., mast cell tryptase), growth factors (NGF), peptides (bradykinin), lipids (prostaglandins), amines (5-hydroxytryptamine), purines (ATP), ions (protons), pressure, and elevated temperature. 2: These factors can activate several classes of receptors and channels expressed by peptidergic nociceptors, including GPCRs, TRP channels, and receptor tyrosine kinases (RTKs). 3: Activated nociceptors release neuropeptides in peripheral tissues, including SP and NKA, which stimulate NK₁Rs on endothelial cells of postcapillary venules and cause plasma extravasation and granulocyte infiltration, and CGRP, which stimulates the calcitonin receptor-like receptor (CLR) on arterioles to cause hyperemia. Together, these changes constitute neurogenic inflammation. 4: If the factors excite nociceptors and generate action potentials, SP and CGRP are also released from the central projections of nociceptors in superficial laminae of the spinal cord dorsal horn, where neuropeptides activate receptors on spinal neurons to transmit painful stimuli centrally.