Functional MRI has been widely used to non-invasively visualize brain function, and response to innocuous and noxious stimulation. In particular, it could serve as an attractive tool to better understand how the brain processes stimuli in mouse models,in which nociception is impaired. Nociceptor-specific knock-out (KO) mice that lack NaV1.7, a Na-channel important for the propagation of action potentials in nociceptors, have been demonstrated to be less sensitive to noxious stimuli:Behavioral and molecular studies in neuropathic pain models revealed a reduction in mechano-sensation, a strong deficit in the development of inflammatory pain, and hyposensitivity to noxious thermal stimulation (1,2).In this study, we characterize the fMRI response to sensory and noxious stimuli in NaV1.7-Wnt1 KO mice using peripheral sensory stimulation paradigms(3).All MRI experiments were conducted using a Bruker Biospec 94/30 small animal MR system (Bruker BioSpin MRI, Germany) operating at 400MHz (9.4T). A four-element receive-only cryogenic phased array coil (Bruker BioSpin AG, Switzerland) was used in combination with a linearly polarized room temperature volume resonator for transmission. Throughout the experiment the animals were intubated, mechanically ventilated, and anesthetized with 1.5% isoflurane in a 20% O₂/80% air mixture. For immobilization pancuronium bromide (Sigma-Aldrich, Germany) was administered i.v. as a bolus at a dose of 1 mg/kg. For the fMRI measurements, data were acquired using a GE-EPI sequence: FOV=16x7 mm² and matrix size=80x35, TE/TR=12/1000ms, NA=1, FA=60°. Twelve adjacent coronal slices with a thickness of 0.5mm were acquired. Animals (n ≥ 5 for each stimulus) were stimulated on forepaw (fp) and hindpaw (hp) using three different paradigms. Electrical stimulation: A pair of needle electrodes was inserted s.c. into the paw. Different current amplitudes (0.5 -1.5 mA) were applied with a pulse duration of 0.5 ms and frequency of 5Hz. The stimulus paradigm consisted of a block design starting with 180s baseline followed by four cycles of 20s stimulus and 120s post-stimulus period. Chemical stimulation: A cannula was inserted s.c. into the paw. Different doses of capsaicin (0.5 and 1µg) were injected. Injection volumes were 5μl (fp) and 10μl (hp). The stimulation paradigm consisted of a 180s baseline and 420s post-injection signal acquisition. Thermal stimulation: A heating plate was attached to the paw. Different temperatures were applied from 40°C to 48°C. The block stimulus paradigm was identical to the paradigm of the electrical stimulation. For analysis, spatial preprocessing of MR data and generation of statistical parametric maps (activity maps) was performed in AFNI (http://afni.nimh.nih.gov/). Maps were generated using the canonical SPM hemodynamic response function with time and dispersion derivatives in a general linear model (GLM). Regions-of-interest (ROIs) were defined according to a stereotaxic mouse brain atlas (4) for the contralateral and ipsilateral primary somatosensory cortex (S1), and BOLD signal time courses extracted. For behavioral investigation the following tests were performed: Von Frey, lick response upon capsaicin injection, withdrawal reflex test using electrical stimulationIn the behavioral tests, in comparison to wildtype (WT) littermates the NaV1.7-Wnt1 KO mice showed reduced sensitivity to three kinds of stimuli applied to the paw: mechanical stimulation (higher pressure was needed to elicit paw withdrawal during Von Frey test), chemical nociceptor stimulation (s.c. injection of capsaicin induced milder licking response), and electrical nerve stimulation (stimulation with 0.5 mA triggered a delayed reflex response in both hindpaw and forepaw) data are shown in Fig.1.In contrast, stimulus-evoked fMRI measurements when using three different stimulus modalities did not reveal differences between the nociceptor-specific KO mice and WT littermates for each of the stimuli applied (Fig. 2).Yet, when applying a chemical stimulus (Capsaicin) we observed dose-dependent and larger evoked BOLD signal changes in the WT littermate compared to the KO group (Fig. 3). Behavioral and fMRI results are summarized in Table 1.The main goal of this study was to characterize the fMRI response to sensory and noxious stimuli in a mouse model (NaV1.7-Wnt1-KO) of impaired nociception (1, 2).However, whereas all applied behavioral tests successfully discriminated between WT and NaV1.7-Wnt1 KO mice, our fMRI experiments did not elucidate, for all stimulus modalities used, differences in evoked BOLD responses between the genotypes.So far, only the administration of a chemical stimulus, yielded different and dose-dependent BOLD responses,i.e. a decreased amplitude in evoked fMRI signal for KO mice.Current fMRI experiments are carried out with modified stimulus paradigms to further verify made observations.Studying NaV1.7-Wnt1 KO mice when subjected to a neuropathic pain model will eventually serve to characterize the evolution of chronic pain development in comparison to WT littermates, and demonstrate whether fMRI procedures are suitable to visualize differences in sensation and perception of pain in mice.