Heat But Not Mechanical Hypersensitivity Depends on Voltage-Gated CaV2.2 Calcium Channel Activity in Peripheral Axon Terminals Innervating Skin.

Voltage-gated CaV2.2 calcium channels are expressed in nociceptors at presynaptic terminals, soma, and axons. CaV2.2 channel inhibitors applied to the spinal cord relieve pain in humans and rodents, especially during pathologic pain, but a biological function of nociceptor CaV2.2 channels in processing of nociception, outside presynaptic terminals in the spinal cord, is underappreciated. Here, we demonstrate that functional CaV2.2 channels in peripheral axons innervating skin are required for capsaicin-induced heat hypersensitivity in male and female mice. We show that CaV2.2 channels in TRPV1-nociceptor endings are activated by capsaicin-induced depolarization and contribute to increased intracellular calcium. Capsaicin induces hypersensitivity of both thermal nociceptors and mechanoreceptors, but only heat hypersensitivity depends on peripheral CaV2.2 channel activity, and especially a cell-type-specific CaV2.2 splice isoform. CaV2.2 channels at peripheral nerve endings might be important therapeutic targets to mitigate certain forms of chronic pain.SIGNIFICANCE STATEMENT It is generally assumed that nociceptor termini in the spinal cord dorsal horn are the functionally significant sites of CaV2.2 channel in control of transmitter release and the transmission of sensory information from the periphery to central sites. We show that peripheral CaV2.2 channels are essential for the classic heat hypersensitivity response to develop in skin following capsaicin exposure. This function of CaV2.2 is highly selective for heat, but not mechanical hypersensitivity induced by capsaicin exposure, and is not a property of closely related CaV2.1 channels. Our findings suggest that interrupting CaV2.2-dependent calcium entry in skin might reduce heat hypersensitivity that develops after noxious heat exposure and may limit the degree of heat hypersensitivity associated with certain other forms of pain.

Assessment of Anhedonia in Adults With and Without Mental Illness: A Systematic Review and Meta-analysis.

Importance: Anhedonia, a reduced capacity for pleasure, is described for many psychiatric and neurologic conditions. However, a decade after the Research Domain Criteria launch, whether anhedonia severity differs between diagnoses is still unclear. Reference values for hedonic capacity in healthy humans are also needed. Objective: To generate and compare reference values for anhedonia levels in adults with and without mental illness. Data Sources: Web of Science, Scopus, PubMed, and Google Scholar were used to list all articles from January 1, 1995 to July 2, 2019, citing the scale development report of a widely used anhedonia questionnaire, the Snaith-Hamilton Pleasure Scale (SHAPS). Searches were conducted from April 5 to 11, 2018, and on July 2, 2019. Study Selection: Studies including healthy patients and those with a verified diagnosis, assessed at baseline or in a no-treatment condition with the complete 14-item SHAPS, were included in this preregistered meta-analysis. Data Extraction and Synthesis: Random-effects models were used to calculate mean SHAPS scores and 95% CIs separately for healthy participants and patients with current major depressive disorder (MDD), past/remitted MDD, bipolar disorder, schizophrenia, substance use disorders, Parkinson disease, and chronic pain. SHAPS scores were compared between groups using meta-regression, and traditional effect size meta-analyses were conducted to estimate differences in SHAPS scores between healthy and patient samples. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Main Outcomes and Measures: Self-reported anhedonia as measured by 2 different formats of the SHAPS (possible ranges, 0-14 and 14-56 points), with higher values on both scales indicating greater anhedonia symptoms. Results: In the available literature (168 articles; 16 494 participants; 8058 [49%] female participants; aged 13-72 years), patients with current MDD, schizophrenia, substance use disorder, Parkinson disease, and chronic pain scored higher on the SHAPS than healthy participants. Within the patient groups, those with current MDD scored considerably higher than all other groups. Patients with remitted MDD scored within the healthy range (g = 0.1). This pattern replicated across SHAPS scoring methods and was consistent across point estimate and effect size analyses. Conclusions and Relevance: The findings of this meta-analysis indicate that the severity of anhedonia may differ across disorders associated with anhedonia. Whereas anhedonia in MDD affects multiple pleasure domains, patients with other conditions may experience decreased enjoyment of only a minority of life's many rewards. These findings have implications for psychiatric taxonomy development, where dimensional approaches are gaining attention. Moreover, the SHAPS reference values presented herein may be useful for researchers and clinicians assessing the efficacy of anhedonia treatments.

The sad weekend: A perilous North American tradition.

Obesity is a global concern and affects millions of Americans who consume poor-quality diets. Diets directly affect the gut microbiota, which can have subsequent effects on inflammation and contribute to other chronic states. Previously we have shown that a Standard American Diet (SAD) increased immune cell activation and prolonged recovery and that a beneficial diet could reduce these negative effects. Here, male and female mice were given access to regular chow (REG), SAD, our Anti-Inflammatory Diet (AID) or a combination of SAD and AID. This latter group was modeled on the commonplace dietary pattern of healthy eating during the week (AID: Monday-Friday) and relaxed eating patterns on the weekend (SAD: Saturday-Sunday). After 14 weeks of diet consumption and an inflammatory injury, we found that the SAD prolonged and the AID promoted recovery. However, recovery was significantly delayed in those mice consuming the AID-SAD, regardless of weekly healthy diet access. In addition, fecal samples taken during the study revealed dramatic differences in microbial community composition, relative abundance of abundant bacterial phyla and alpha diversity. These data confirm the impact of diet on gut microbiota and suggest a relation between abundance of specific bacterial taxa and susceptibility to prolonged recovery from injury.