Post-traumatic morbidity reduces the quality of life for traumatic brain injury (TBI) survivors by altering neuropsychological function. After midline fluid percussion injury (FPI), diffuse pathology in the ventral posterior thalamus suggests that somatosensory whisker function may be impaired post-injury. The goals of the present study were to design and validate a task to detect injury-induced somatosensory morbidity (Experiment 1), and to evaluate preliminary applications of the task (Experiment 2). In Experiment 1, male Sprague-Dawley rats were subjected to moderate FPI (*1.9 atm) or sham injury. Over an 8-week time course, the whiskers on both mystacial pads were stimulated manually with an applicator stick in an open field for three 5-min periods. Behavioral responses in this whisker nuisance task were recorded using objective criteria (max score ¼ 16). Sham animals were ambivalent or soothed by whisker stimulation (4.0 AE 0.8), whereas brain-injured rats showed aggravated responses at 1 week (6.7 AE 0.9), which became significant at 4 weeks (9.5 AE 0.5) and 8 weeks (8.4 AE 1.1) compared to sham injury, indicating chronic injury-induced sensory sensitivity. Total free serum corticosterone levels indicated a significant stress response in brain-injured (125.0 AE 17.7 ng=mL), but not uninjured animals (74.2 AE 12.2 ng=mL) in response to whisker stimulation. In Experiment 2, to evaluate applications of the whisker nuisance task, four additional uninjured and brain-injured groups were subjected to mild brain injury only, shaved whiskers after moderate brain injury, repeated whisker nuisance task stimulation after moderate brain injury, or regular opportunities for tactile exploration of an enriched environment after moderate brain injury over 4 weeks post-injury. The whisker nuisance task has the sensitivity to detect mild brain injury (7.7 AE 1.0), but morbidity was not mitigated by any of the neurorehabilitative interventions. Following diffuse brain injury, the whisker nuisance task is a promising tool to detect post-traumatic morbidity and the efficacy of therapeutic interventions that may restore discrete circuit function in brain-injured patients.

Systemic administration of thiazolidinediones reduces peripheral inflammation in vivo, presumably by acting at peroxisome proliferator-activated receptor γ (PPARγ) in peripheral tissues. Based on a rapidly growing body of literature indicating the CNS as a functional target of PPARγ actions, we postulated that brain PPARγ modulates peripheral edema and the processing of inflammatory pain signals in the dorsal horn of the spinal cord. To test this in the plantar carrageenan model of inflammatory pain, we measured paw edema, heat hyperalgesia, and dorsal horn expression of the immediate-early gene c-fos after intracerebroventricular (ICV) administration of PPARγ ligands or vehicle. We found that ICV rosiglitazone (0.5-50 µg) or 15d-PGJ 2 (50-200 µg), but not vehicle, dose-dependently reduced paw thickness, paw volume and behavioral withdrawal responses to noxious heat. These anti-inflammatory and anti-hyperalgesia effects result from direct actions in the brain and not diffusion to other sites, because intraperitoneal and intrathecal administration of rosiglitazone (50 µg) and 15d-PGJ 2 (200 µg) had no effect. PPARγ agonists changed neither overt behavior nor motor coordination, indicating that non-specific behavioral effects do not contribute to PPAR ligand-induced anti-hyperalgesia. ICV administration of structurally dissimilar PPARγ antagonists (either GW9662 or BADGE) reversed the anti-inflammatory and anti-hyperalgesic actions of both rosiglitazone and 15d-PGJ 2 . To evaluate the effects of PPARγ agonists on a classic marker of noxious stimulus-evoked gene expression, we quantified Fos protein expression in the dorsal horn. The number of carrageenan-induced Fos-like immunoreactive profiles was less in rosiglitazone-treated rats as compared to vehicle controls. We conclude that pharmacological activation of PPARγ in the brain rapidly inhibits local edema and the spinal transmission of noxious inflammatory signals.