Trigeminal Pain Responses in Obese ob/ob Mice Are Modality-Specific.

How obesity exacerbates migraine and other pain disorders remains unknown. Trigeminal nociceptive processing, crucial in migraine pathophysiology, is abnormal in mice with diet induced obesity. However, it is not known if this is also true in genetic models of obesity. We hypothesized that obese mice, regardless of the model, have trigeminal hyperalgesia. To test this, we first evaluated trigeminal thermal nociception in leptin deficient (ob/ob) and control mice using an operant thermal assay. Unexpectedly, we found significant hypoalgesia in ob/ob mice. Because thermal hypoalgesia also occurs in mice lacking the transient receptor potential vanilloid 1 channel (TRPV1), we tested capsaicin-evoked trigeminal nociception. Ob/ob and control mice had similar capsaicin-evoked nocifensive behaviors, but ob/ob mice were significantly less active after a facial injection of capsaicin than were diet-induced obese mice or lean controls. Conditioned place aversion in response to trigeminal stimulation with capsaicin was similar in both genotypes, indicating normal negative affect and pain avoidance. Supporting this, we found no difference in TRPV1 expression in the trigeminal ganglia of ob/ob and control mice. Finally, we assessed the possible contribution of hyperphagia, a hallmark of leptin deficiency, to the behavior observed in the operant assay. Ob/ob and lean control mice had similar reduction of intake when quinine or capsaicin was added to the sweetened milk, excluding a significant contribution of hyperphagia. In summary, ob/ob mice, unlike mice with diet-induced obesity, have trigeminal thermal hypoalgesia but normal responses to capsaicin, suggesting specificity in the mechanisms by which leptin acts in pain processing.

An Aptamer-based Sensor for Unchelated Gadolinium(III).

A method for determining the presence of unchelated trivalent gadolinium ion (Gd3+) in aqueous solution is demonstrated. Gd3+ is often present in samples of gadolinium-based contrast agents as a result of incomplete reactions between the ligand and the ion, or as a dissociation product. Since the ion is toxic, its detection is of critical importance. Herein, the design and usage of an aptamer-based sensor (Gd-sensor) for Gd3+ are described. The sensor produces a fluorescence change in response to increasing concentrations of the ion, and has a limit of detection in the nanomolar range (~100 nM with a signal-to-noise ratio of 3). The assay may be run in an aqueous buffer at ambient pH (~7 - 7.4) in a 384-well microplate. The sensor is relatively unreactive toward other physiologically relevant metal ions such as sodium, potassium, and calcium ions, although it is not specific for Gd3+ over other trivalent lanthanides such as europium(III) and terbium(III). Nevertheless, the lanthanides are not commonly found in contrast agents or the biological systems, and the sensor may therefore be used to selectively determine unchelated Gd3+ in aqueous conditions.

Abnormal trigeminal sensory processing in obese mice.

Obesity is associated with several pain disorders including headache. The effects of obesity on the trigeminal nociceptive system, which mediates headache, remain unknown. We used 2 complementary mouse models of obesity (high-fat diet and leptin deficiency) to examine this. We assessed capsaicin-induced nocifensive behavior and photophobia in obese and control mice. Calcium imaging was used to determine the effects of obesity on the activity of primary trigeminal afferents in vitro. We found that obese mice had a normal acute response to a facial injection of capsaicin, but they developed photophobic behavior at doses that had no effect on control mice. We observed higher calcium influx in cultured trigeminal ganglia neurons from obese mice and a higher percentage of medium to large diameter capsaicin-responsive cells. These findings demonstrate that obesity results in functional changes in the trigeminal system that may contribute to abnormal sensory processing. Our findings provide the foundation for in-depth studies to improve the understanding of the effects of obesity on the trigeminal system and may have implications for the pathophysiology of headache disorders.