All animals, including humans, experience injury, and every species examined shows adaptive responses to help avoid injury or re-injury. Injury to humans causes pain, which can be long lasting (even permanent) and sometimes untreatable. Although much has been learned about other aspects of human biology through comparative studies of simpler animals, including selected invertebrates, systematic comparative studies of behavioral and neural responses to injury in invertebrates have been lacking. This project will compare behavioral and neural responses to peripheral injury in two invertebrates that, because of their giant neurons, have been sources of pioneering discoveries in neuroscience: the common Atlantic squid, Loligo, and a large marine snail, Aplysia. Both are molluscs, but they have very different life styles and cognitive capabilities. Hypotheses to be tested include: (1) In the peripheral sensory neurons of both species, injury-induced, long-lasting behavioral sensitization involves a similar long-term enhancement of responsiveness that resembles the effects reported in mammals, (2) these changes are induced by common chemical signals that also drive inflammatory pain in mammals, (3) the large-brained squid, but not small-brained snail display ongoing awareness of an injury, and (4) sensitization of defensive responses in the squid increases the chances of survival in a wounded state by decreasing the vulnerability to predatory attacks. The broader impacts of this research project will be the encouragement of the use of molluscs to explore the evolution of fundamental behavioral patterns involving core mechanisms that are widely conserved and may be important for human pain, and the education of future scientists (including undergraduates) interested in comparative and evolutionary approaches to behavioral neurobiology. The resulting scientific information will be published in scientific journals and disseminated to foster rational and humane treatment of molluscs and other invertebrates in research.