Upon perception of a noxious stimulus, an organism executes defense mechanisms, such as escape responses. The molecular basis of these mechanisms is poorly understood. In this paper we show that upon exposure to noxious temperature, Caenorhabditis elegans reacts by a withdrawal reflex. To analyze this thermal avoidance behavior, we developed a laser-based assay to quantify the response. The escape reflex can be observed in 98% of the adult animals, but is not executed in animals in diapause. The thermal avoidance response differs significantly from the thermotaxis behavior that is based on the perception of physiological temperature. It involves different neurons and is influenced by mutations in distinct genes. As in mammals, the strength of the thermal avoidance response is increased by application of capsaicin, the pungent ingredient in chili peppers. We find that thermal avoidance is strongly reduced in mutants affecting the neural transmission modulated by glutamate and neuropeptides as well as in mutants affecting the structure and function of sensory neurons. We suggest that the study of this nociceptive behavior in C. elegans can be used to understand the genetic and molecular basis of thermal nociception.Every organism depends on a set of regulatory, protective behaviors to ensure survival. Upon exposure to a noxious mechanical, chemical, or thermal stimulus, animals execute a protective withdrawal-reflex program to prevent cellular damage. In the central nervous system, aversive and protective reactions to these stimuli include the sensation of pain. Whereas the perception of pain may be silenced during anesthesia, nociceptive reflexes by the peripheral nervous system are still executed (1).In vertebrates, the presence of tissue-damaging stimuli or the existence of tissue damage are sensed by primary afferent neurons. These, in general, respond only to high intensities of a stimulus and correspond either to a single sensory modality or are polymodal (are stimulated, for example, by mechanical or thermal stimuli). Several animal and in vitro models have been established to study the physiological and pharmacological parameters that interfere with pain perception and nociception. Recently, cell culture experiments suggested that the vanilloid receptor VR1 is activated both by capsaicin and by noxious heat (2, 3). VR1 belongs to the evolutionary conserved TRP (transient receptor potential) family of nonselective ion channels and is located in sensory nerve endings of the dorsal root ganglion. Despite this finding, little is known about the molecular mechanisms of nociception.The nematode Caenorhabditis elegans is an excellent organism in which to study the behavioral responses to noxious environmental stimuli. Its powerful genetics and the simple nervous system have greatly facilitated the identification of the neural circuits and genes involved in various avoidance reactions such as its response to noxious chemicals, high osmolarities, acidic pH (4), and noxious mechanical stimuli (5).We show her...