Date of Award
Doctor of Philosophy (PhD)
The treatment of chronic pain is an immense clinical and societal burden rooted in the ineffectiveness and adverse side effects of existing analgesics. Extensive efforts have been directed towards the development of novel pain therapies with maximal efficacy and minimal unwanted effects; however, putative therapeutic targets identified in preclinical rodent models rarely translate in clinical trials. The poor translational record of basic pain research findings has been attributed, in part, to the use of suboptimal rodent pain models and behavioral endpoints used to assess putative analgesics, as well as differences in the pharmacological profiles of rodents and humans. The work presented in this thesis aims to address these limitations.
Human pain is defined as a complex sensory and emotional experience, yet rodent pain models have historically used reflex/withdrawal measures of hypersensitivity as the primary outcome. To address this limitation, the first study of this thesis evaluates more complex, voluntary behaviors as indicators of pain-like behavior in rodents. We found that inflammation and nerve injury minimally interfere with physical activity (voluntary wheel running, locomotion, and gait), social interaction, or anxiety-like behavior in mice, indicating that these voluntary behaviors are not reliable pain-related readouts across rodent injury models. As recent findings from other groups align with our results, we further conclude that in contrast to humans, changes in these voluntary behaviors are not characteristic of persistent pain in mice.
Although rodents and humans possess different pharmacological profiles, putative analgesics are oftentimes identified and exclusively evaluated in rodent tissues and/or pain models prior to entering clinical trials. In response to this translational gap, we recently developed a protocol to surgically extract dorsal root ganglia from deceased human organ donors and subsequently culture sensory neurons. In the second study of this thesis, we utilize human sensory neurons to assess the translational potential of targeting metabotropic glutamate receptors 2 and 3 (mGluR2/3), which have been identified as modulators of pain in a variety of rodent models. In mouse sensory neurons, we found that activation of mGluR2/3 blocked inflammation-induced sensitization of the nonselective cation channel TRPV1. In contrast, this effect was not observed in human sensory neurons. These results indicate that mechanisms of peripheral analgesia are not entirely conserved across species. More broadly, our findings demonstrate that using human tissue to validate analgesic targets identified in rodents is an important step in the translational research process.
Due to poor pain relief from current pharmacological therapies, exercise has been explored as an alternative, nonpharmacological intervention for chronic pain. Indeed, exercise has been shown to improve patient pain ratings and functionality, albeit via largely unknown mechanisms. In the final study of this thesis, we evaluated whether voluntary exercise similarly reduced pain-like behavior in mice, with the goal of using a mouse model to elucidate the molecular mechanisms mediating clinical exercise-induced analgesia. However, we found that voluntary wheel running did not reduce pain-like behavior in common rodent models of inflammation and nerve injury. Previous preclinical studies of exercise-induced analgesia utilized forced exercise paradigms, and thus our findings suggest that voluntary and forced exercise may have different analgesic potential in rodents.
Taken together, there are a variety of existing experimental limitations that can be addressed to increase the translatability of basic pain research. Based on our current findings, we conclude that voluntary rodent behavioral endpoints modeled off of the human chronic pain experience have limited utility. In contrast, confirming preclinical findings in human tissue represents a promising approach to bridge the translational gap between rodent and human pain research.
Chair and Committee
Robert W. Gereau
Yu-Qing Cao, Erik D. Herzog, Qin Liu, Durga P. Mohapatra,
Sheahan, Tayler Diane, "Bridging the translational gap between rodent and human pain research" (2017). Arts & Sciences Electronic Theses and Dissertations. 1197.