The Use of Zebrafish as a Non-traditional Model Organism in Translational Pain Research: The Knowns and the Unknowns

Abstract

The ability of the nervous system to detect a wide range of noxious stimuli is crucial to avoid life-threatening injury and to trigger protective behavioral and physiological responses. Pain represents a complex phenomenon, including nociception associated with cognitive and emotional processing. Animal experimental models have been developed to understand the mechanisms involved in pain response, as well as to discover novel pharmacological and non-pharmacological anti-pain therapies. Due to the genetic tractability, similar physiology, low cost, and rich behavioral repertoire, the zebrafish (Danio rerio) is a powerful aquatic model for modeling pain responses. Here, we summarize the molecular machinery of zebrafish responses to painful stimuli, as well as emphasize how zebrafish-based pain models have been successfully used to understand specific molecular, physiological, and behavioral changes following different algogens and/or noxious stimuli (e.g., acetic acid, formalin, histamine, Complete Freund's Adjuvant, cinnamaldehyde, allyl isothiocyanate, and fin clipping). We also discuss recent advances in zebrafish-based studies and outline the potential advantages and limitations of the existing models to examine the mechanisms underlying pain responses from evolutionary and translational perspectives. Finally, we outline how zebrafish models can represent emergent tools to explore pain behaviors and pain-related mood disorders, as well as to facilitate analgesic therapy screening in translational pain research.

Keywords: Non-traditional pain models; anti-pain medication screening; nociceptors; noxious stimuli; pain-related behaviors; zebrafish.

Fig. (1)

General advantages and molecular features of zebrafish in translational pain research. As a vertebrate species, the zebrafish shows a high genetic and physiological homology when compared to mammals, but present a low cost of maintenance and feasibility to high-throughput screens similar to invertebrates (left). Molecular correspondece of the receptors involved in pain responses in humans with their respective genes in zebrafish (right). # are absent in zebrafish. *are splice variants.

Fig. (2)

Common experimental protocols used to assess pain in adult zebrafish with the respective behavioral endpoints measured in different studies depicted in timeline perspective. References: Reilly et al. [42], Maximino [52], Correia et al. [196], Schroeder et al. [185], Taylor et al. [33], Costa et al. [34], Thomsom et al. [35].