# Development and Validation of a Clinically Relevant Animal Pain Model

> **NIH NIH R33** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $388,584

## Abstract

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.
Succes...

## Key facts

- **NIH application ID:** 10460795
- **Project number:** 4R33NS116423-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Shiqian Shen
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,584
- **Award type:** 4N
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460795

## Citation

> US National Institutes of Health, RePORTER application 10460795, Development and Validation of a Clinically Relevant Animal Pain Model (4R33NS116423-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10460795. Licensed CC0.

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