One key barrier in developing safe and effective pain treatment drugs is that there are critical gaps between animal pain models and pain in humans. These gaps lie in three main categories. 1) Construct validity. There is fundamental difference in the site of nerve injury between animal pain models and clinical pain conditions. 2) Content validity. Human neuropathic pain including trigeminal neuralgia often presents with spontaneous pain, with only about 20% of patients reporting mechanical hypersensitivity. In contrast, pain in animal models often manifests as evoked behaviors such as mechanical and thermal hypersensitivities. Besides spontaneous pain, many key clinical presentations of pain, such as dental pain symptoms in trigeminal neuralgia, are not recapitulated by existing trigeminal pain models. 3) Criterion validity. Clinical pain assessment is based on patient reported symptoms and functional assessment, with a consideration of pain-induced affective changes. Whereas, in non-verbalizing animals, pain assessment is typically based on spinal reflexes. To improve criterion validity of animal pain models, it is imperative to establish behavioral indices that allow objective and quantitative measurements, reflecting both functional and affective status. In preliminary studies, we constructed a mouse model of trigeminal nerve root compression (Com-TN) by administering surgifoam through the foramen lacerum at the skull base of mice. Our data indicate that the Com-TN model provides improved construct, content, and criterion validities when compared with infraorbital nerve ligation model. More specifically, Com-TN model has construct validity as the site of compression mimics which in human trigeminal neuralgia. Its content validity is supported by spontaneous pain behaviors including excessive facial grooming, asymmetrical facial grimaces and, more importantly, spontaneous and synchronized neuronal activities in somatosensory S1 cortex by two- photon microscopy in awake and resting state. Additionally, content validity is supported by recapitulating clinical presentations of trigeminal neuralgia, including dental pain and pain-induced depression behavior. The criterion validity is supported by several pain-related behaviors, which can be assessed objectively and quantitively to reflect functional and affective aspects of pain. Data also suggest that it has predictive validity as carbamazepine, a first-line treatment for trigeminal neuralgia, partially alleviated pain behaviors. To further develop and validate the Com-TN model, we plan to carry out two phases of studies: R61 phase - 1) to establish the Com-TN model in female mice; 2) to establish the optimal dose of surgifoam; and 3) to determine the dynamic ranges and reliability of the behavior endpoints. R33 Phase - 1) to establish the Com-TN model in another institute; 2) to establish the model in SD rats and CD1 mice; and 3) to investigate the predictive validity of the Com-TN model. Successful execution of this proposal will establish a pain model which enables multi-dimensional pain assessment in an objective and quantitative manner. The outcomes of this proposal will fill in the critical gaps between animal pain models and pain in humans, to provide a testing platform for drug development.
The purpose of this grant application is to establish a clinically relevant trigeminal pain model, with construct, content and criterion validities, which enables objective and quantitative pain measurements. The outcomes of this proposal will fill in the critical gaps between animal pain models and clinical pain condition, to provide a testing platform for drug development.
