Brief, noxious, electrical or mechanical stimulation of the skin of Aplysia produces enhancement of defensive reflexes triggered at the same site for at least a week after the noxious stimulation. This site- specific behavioral sensitization can be expressed as an increase in duration of the siphon-withdrawal reflex and as an increase in magnitude of the tail-withdrawal reflex. It is unlikely that peripheral factors play a predominant role in the long-term memory. First, long- term enhancement is blocked when the CNS is disconnected from the noxious stimulation site by nerve transection. Second, long-term enhancement is blocked by preventing neural activation at the noxious stimulation site, indicating that persistent physical damage alone is insufficient to cause the enhancement. A role for activity-dependent extrinsic modulation (ADEM) of mechanosensory neurons is suggested by similar site-specific enhancement produced when weak sensory activation is paired with general modulation elicited by strong stimulation of a distant site. Because this pairing represents a form of classical conditioning, site-specific sensitization and cutaneous classical conditioning appear to be closely related in this system. These findings suggest that site-specific sensitization reflects, at least in part, a central, long-term memory of injury. This form of memory may be phylogenetically widespread, and functionally similar to aspects of hyperalgesia. In addition, the close relationship between site-specific sensitization and cutaneous classical conditioning supports the hypothesis that some forms of classical conditioning evolved from mechanisms of sensitization.