Pain is often associated with clinically relevant depression of behavior and mood, and relief of pain-related depression is a common goal of treatment in both human and veterinary medicine. In the development of pharmacological compounds to treat pain and related depression, preclinical studies may be used to evaluate the analgesic potential of new drugs. Such studies require reliable, accurate assays of pain-related behavioral depression in animals. Intracranial self-stimulation (ICSS) is a type of operant conditioning procedure that produces stable baseline behavioral response rates. The author reviews recent research on the use of ICSS to evaluate the expression and pharmacological modulation of pain-related behavioral depression in rats. Results suggest that assays of pain-depressed behavior using ICSS may serve as a useful new tool to improve the translation of preclinical findings to clinical results in analgesic drug development.