Discovering chronic pain treatments: better animal models might help us get there

Traditionally, modeling pain conditions in animals — usually rodents — involves the use of chemical or surgical interventions or repeated exposure to an environmental stressor (12, 13). Researchers typically perform such interventions in rodent strains such as the Sprague Dawley rat or the C57BL/6 mouse, which do not have a genetic susceptibility to pain. This practice limits the applicability of findings to humans, as many pain syndromes arise spontaneously without apparent precipitating factors. In response to the national discussion, there have been several rodent models developed recently with an eye to improving face validity (defined as the similarity in clinical signs and symptoms), construct validity (defined as similarity in pathophysiologic disease mechanisms), and predictive validity (defined as the relative effectiveness of various clinical interventions being mimicked by the model). Among these systems, models of complex regional pain syndrome (CPRS) (15), complex orthopedic trauma (16), temporomandibular joint pain (17), and a genetic model of widespread hyperalgesia (18) have been used effectively to determine pathophysiological mechanisms associated with these conditions.

In this issue of the JCI, Ding, Fischer, and co-authors (19) describe a different trigeminal neuropathic pain model that exhibits several key features that have been on investigators’ wish lists for years, including (a) face validity: the foramen lacerum impingement of trigeminal nerve root (FLIT) model exhibits robust spontaneous pain behaviors (facial grimacing, excessive facial grooming, intermittent eye squinting) and clinically relevant functional consequences of persistent pain (body weight loss, decreased wood chewing, soft food preference, increased incisor length, increased anxiety behaviors, and sexual dysfunction), which are consistent with the clinical signs and symptoms of human trigeminal neuralgia (TN); (b) construct validity: the FLIT model utilizes a clever, reversible trigeminal nerve root compression that mimics the human pathology of trigeminal nerve root impingement at its entry zone (20); and (c) predictive validity, which includes nearly complete ineffectiveness of NSAIDS, partial effectiveness of carbamazepine, and robust effectiveness of trigeminal nerve root decompression surgery, a definitive treatment for patients with TN with vascular compression (21).

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