Large Animal Models for Pain Therapeutic Development

The humane use of preclinical animal models plays a critical role both in understanding the basic biology of pain as well as in the development of therapeutic treatments to alleviate pain. Clinically relevant pain is the result of complex processes involving peripheral transduction and transmission as well as central modulation and processing that leads to the final conscious sensation of pain. Much has been learned about the mechanisms underlying the transduction and transmission of the pain signal within the nervous system through the use of cellular, biochemical, and molecular techniques (Millan 1999; Scholz and Woolf 2007; Zeilhofer 2005). However, understanding the actual experience of pain will always require an intact organism that can integrate the full range of external stimuli and internal cognitive and emotional states that drive and modulate pain. Rodent models of pain have historically played a dominant role in the study of pain mechanisms (Negus et al. 2006; Walker et al. 1999). There are many good reasons for this, including the practicalities of low cost, simplified ethical concerns, and the scientific value of having a large database of prior research to provide context for new findings. A large historical database is particularly important in the field of drug discovery and development since the sensitivity and predictive validity of animal models can only be established through extensive testing in many contexts. For these reasons, the rat and mouse models will continue to be the workhorses driving basic research as well as drug discovery. Unfortunately, there are many ways that the biology of rodents may fail to accurately predict the biology and pharmacology of clinical pain conditions in humans (Blackburn -Munro 2004; Le Bars et al. 2001). Given the high cost of developing new therapeutics (Adams and Brantner 2006), there is a growing need to validate biological and pharmacological findings in non-rodent species that, while perhaps less tractable than rodents, address known or ill-defined differences between mice and men. It is hoped that through the humane study and evaluation of pain states in higher order preclinical species, we can better predict whether biological mechanisms and specific compounds have relevance for clinical pain. Ultimately, well-validated pain models in non-rodent species could enhance the speed, reduce the costs, and increase the probability of the successful development of new analgesic therapeutics offering enhanced efficacy and reduced adverse effects. This chapter will review the gaps in current pain research using rodent models that may potentially be addressed using preclinical animal models of pain in higher species. Additionally, we will review the pain models and assessments that have been developed to date in “higher” and larger species and highlight areas where there is a need for the development of new models and methods of pain assessment.