Substance P and the inflammatory and immune response.

These findings suggest that SP may have proinflammatory actions in both the peripheral tissue and the central nervous system after tissue injury. Although the possibility that the same neuropeptide could have actions in both the brain and the peripheral tissues is certainly not without precedent, there is a key difference in the source of the ligand in these tissues. Unlike peripheral tissues such as the gastrointestinal tract or skin, where there is a dense innervation by SP-containing dorsal root ganglion neurons, the brain lacks such a sensory innervation. This important difference raises the question as to the possible origin of the SP that could occupy the SP receptors expressed by the CNS glia after neuronal injury. Whereas the answer to this question is currently unknown, an important clue may be the findings that circulating leukocytes have been reported to synthesize neuropeptides such as ACTH, opiates, and SP. To begin to fully understand the role that SP may play in coordinating the inflammatory and immune response to tissue injury, we must first understand where SP fits into the cascade of events that occur after tissue injury, what events lead to nociceptor sensitization (which may lead to an increase in SP release), and what regulates SP receptor expression (which may be involved in the direction of leukocytes to the site of injury, plasma extravasation, or the proliferation/hypertrophy of reactive astrocytes). Although this may seem like a daunting task, several recent advances including the cloning of the three mammalian tachykinin receptors and the introduction of highly potent and specific SP receptor antagonists should make this a highly fruitful field of investigation.