Nociceptor sensitization is partly mediated by the release of toxic substances (potassium, prostaglandin, bradykinins, and substance P) from damaged tissue. Those toxic substances excite nociceptors and increase their sensitivity to pain (hyperalgesia). Substance P, released by an axon reflex, induces vasodilation and mast-cell degranulation leading to histamine and serotonin release. These inflammatory agents sensitize damaged tissue and surrounding nociceptors even further prolonging the hypersensitivity state (secondary hyperalgesia).