This article examines the neuromodulatory mechanisms associated with predator recognition and responses in a mainland and an island population of deer mice, Peromyscus maniculatus. In a weasel-sympatric mainland population of deer mice, P. m. artemisiae, a 30-s exposure to the presence (scent) of the short-tailed weasel (Mustela erminea) elicited immediate and relatively short-lasting increases in the latency of response to aversive stimuli. These enhanced nociceptive thresholds (analgesic responses) were mediated by benzodiazepine-sensitive mechanisms that have been associated with the mediation of fear and fright behaviors and antipredator defensive mechanisms. A 5-min exposure of the mainland animals to the weasel elicited an analgesic response that was both benzodiazepine (BDZ) and opioid sensitive, while 15-min exposures induced only the relatively prolonged opioid-mediated analgesic responses. Opioid activation and opioid-mediated behavioral responses are generally associated with exposure to stressful stimuli. In contrast to the predominately BDZ-sensitive responses of the mainland animals, both brief and longer exposures of an island (predator-free) population of deer mice, P. m. artemisiae, to a weasel elicited only the delayed and more prolonged opioid-mediated analgesic response. Exposure for either 5 or 15 min to a nonpredator, the European rabbit (Oryctolagus cuniculus), induced only opioid-mediated analgesic responses in both of the populations of mice. These results demonstrate the existence of population differences in the responses of deer mice to a predator. These findings also suggest that the population differences in responses may be related to a differential activation and/or expression of BDZ and opioid-sensitive mechanisms.