Separate populations of neurons in the rostral ventromedial medulla project to the spinal cord and to the dorsolateral pons in the rat

Activation of neurons in the rostral ventromedial medulla (RVM) directly modulates spinal nociceptive transmission by projections to the spinal cord dorsal horn and indirectly by projections to neurons in the dorsolateral pons (DLP) that project to the spinal cord dorsal horn. However, it is not known whether the same neurons in the RVM produce both direct and indirect modulation of nociception. Deposits of the retrograde tracers Fluoro-Gold (FG) in the spinal cord dorsal horn and DiI in the DLP were used to determine whether the same RVM neurons project to both of these regions. Only 0.9+/-0.1% of RVM neurons retrogradely labeled with Fluoro-Gold from the spinal cord were also labeled with DiI placed in the DLP. In addition, spinally projecting RVM neurons were significantly larger than RVM neurons that project to the DLP. Finally, spinally projecting neurons were found predominantly on the midline and within the RVM; neurons that project to the DLP had a wider distribution and were present both within and outside of the RVM. Thus, separate and morphologically distinct populations of RVM neurons appear to modulate nociception by direct and indirect descending pathways

Possible Drug-Associated Sialolithiasis by the Bicarbonate Anhydrase Inhibitor Topiramate: A Case Report and Literature Review

Topiramate is an antiepileptic drug indicated for the treatment of seizure disorders, migraine prophylaxis, and more recently, for weight loss. This new indication will likely increase use of this agent significantly. As a carbonic anhydrase inhibitor, topiramate can affect the pH of bodily fluids, and is known to increase risk of nephrolithiasis. However, as discussed here, these properties also result in an as so far unaddressed risk for development of sialoliths, calcified stones formed in the salivary duct or glands. The physiological mechanisms for stone development in the salivary gland are reviewed, and the pharmacological effects of topiramate on sialolith formation are discussed. This report describes a female patient treated with topiramate for migraine prophylaxis who subsequently presented with a sialolith in the left submandibular duct. Disclosures: This study did not receive any sponsorship or funding from the industry, government, or institution within the last 2 years and during the time in which the case was written and reviewed

Electrophysiological Heterogeneity of Spinally-Projecting Serotonergic and Non-Serotonergic Neurons in the Rostral Ventromedial Medulla

This study examined the passive membrane and action potential properties of serotonergic and nonserotonergic neurons in the rostral ventromedial medulla (RVM) of the rat using whole cell patch-clamp recording techniques in the slice. Serotonergic neurons were identified by immunoreactivity for tryptophan hydroxylase (TrpH). Spinally projecting neurons were retrogradely labeled with 1\u27-dioactadecyl-3,3,3\u27,3\u27-tetramethylindocarbodyanine perchlorate (DiI). Three types of neurons were identified within both spinally projecting serotonergic and nonserotonergic populations. Type 1 neurons exhibited irregular or sporadic spontaneous activity interspersed with periods of quiescence. Type 2 neurons were not spontaneously active and were additionally discriminated by a more negative resting membrane potential and a larger-amplitude action potential. Type 3 neurons fired repetitively without pause. Serotonergic neurons had a higher membrane resistance and greater action potential half-width than their nonserotonergic counterparts and rarely exhibited a fast afterhyperpolarization. Serotonergic type 3 neurons also fired more slowly and regularly than nonserotonergic type 3 neurons. Comparison of electrophysiological and immunohistochemical characteristics suggested that the smallest type 3 serotonergic neurons had an increased risk of immunohistochemical misclassification due to failure to detect TrpH, possibly due to more complete dialysis of intracellular contents during lengthy recordings. This risk was minimal for type 1 or 2 serotonergic neurons. The three different types of spinally projecting serotonergic neurons also differed markedly in their responsiveness to the mu opioid receptor agonist D-Ala2, NMePhe4, Gly5-ol]enkephalin. These results provide important new electrophysiological and pharmacological evidence for a significant heterogeneity among spinally projecting serotonergic RVM neurons. They may also provide a basis for resolving the controversy concerning the role of serotonergic RVM neurons in opioid analgesia

Role of spinal GABA receptors in the acute antinociceptive response of mice to hyperbaric oxygen

•HBO2-induced antinociception is mediated by spinal GABAA but not GABAB receptors.•Acetic acid reduced expression of nNOS and GABAA β3pSER 408/409.•HBO2 treatment restored nNOS and GABAA β3pSER 408/409 expression to control levels.•Protein expression was altered in lumbar but not thoracic spinal cord. New pain treatments are in demand due to the pervasive nature of pain conditions. Hyperbaric oxygen (HBO2) has shown potential in treating pain in both clinical and preclinical settings, although the mechanism of this effect is still unknown. The aim of this study was to investigate whether the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) is involved in HBO2-induced antinociception in the central nervous system (CNS). To accomplish this goal, pharmacological interactions between GABA drugs and HBO2 were investigated using the behavioral acetic acid abdominal constriction test. Western blotting was used to quantify protein changes that might occur as a result of the interactions. GABAA but not GABAB receptor antagonists dose-dependently reduced HBO2 antinociception, while antagonism of the GABA reuptake transporter enhanced this effect. Western blot results showed an interaction between the pain stimulus and HBO2 on expression of the phosphorylated β3 subunit of the GABAA receptor at S408/409 in homogenates of the lumbar but not thoracic spinal cord. A significant interaction was also found in neuronal nitric oxide synthase (nNOS) expression in the lumbar but not thoracic spinal cord. These findings support the notion that GABA may be involved in HBO2-induced antinociception at the GABAA receptor but indicate that more study will be needed to understand the intricacies of this interaction

Learning Bridge: Curricular Integration of Didactic and Experiential Education

Objectives. To assess the impact of a program to integrate introductory pharmacy practice experiences with pharmaceutical science topics by promoting active learning, self-directed learning skills, and critical-thinking skills. Design. The Learning Bridge, a curriculum program, was created to better integrate the material first-year (P1) students learned in pharmaceutical science courses into their introductory pharmacy practice experiences. Four Learning Bridge assignments required students to interact with their preceptors and answer questions relating to the pharmaceutical science material concurrently covered in their didactic courses. Assessment. Surveys of students and preceptors were conducted to measure the effectiveness of the Learning Bridge process. Feedback indicated the Learning Bridge promoted students’ interaction with their preceptors as well as development of active learning, self-directed learning, and critical-thinking skills. Students also indicated that the Learning Bridge assignments increased their learning, knowledge of drug information, and comprehension of relevant data in package inserts. Conclusion. The Learning Bridge process integrated the didactic and experiential components of the curriculum, enhancing student learning in both areas, and offered students educational opportunities to interact more with their preceptors