Deciphering migraine pain mechanisms through electrophysiological insights of trigeminal ganglion neurons

Abstract Migraine is a complex neurological disorder that affects millions of people worldwide. Despite extensive research, the underlying mechanisms that drive migraine pain and related abnormal sensation symptoms, such as hyperalgesia, allodynia, hyperesthesia, and paresthesia, remain poorly understood. One of the proposed mechanisms is cortical spreading depression (CSD), which is believed to be involved in the regulation of trigeminovascular pathways by sensitizing the pain pathway. Another mechanism is serotonin depletion, which is implicated in many neurological disorders and has been shown to exacerbate CSD-evoked pain at the cortical level. However, the effects of CSD and serotonin depletion on trigeminal ganglion neurons, which play a critical role in pain signal transmission, have not been thoroughly studied. In this study, we aimed to investigate the association between CSD and serotonin depletion with peripheral sensitization processes in nociceptive small-to-medium (SM) and large (L) -sized trigeminal ganglion neurons at the electrophysiological level using rat models. We divided the rats into four groups: the control group, the CSD group, the serotonin depletion group, and the CSD/serotonin depletion group. We induced CSD by placing KCl on a burr hole and serotonin depletion by intraperitoneal injection of PCPA (para-chlorophenoxyacetic acid). We then isolated trigeminal ganglion neurons from all groups and classified them according to size. Using patch-clamp recording, we recorded the excitability parameters and action potential (AP) properties of the collected neurons. Our results showed that in SM-sized trigeminal ganglion neurons, the CSD-SM and CSD/serotonin depletion groups had a higher positive resting membrane potential (RMP) than the control-SM group (p = 0.001 and p = 0.002, respectively, post-hoc Tukey’s test). In addition, the gap between RMP and threshold in the CSD-SM group was significantly narrower than in the control-SM group (p = 0.043, post-hoc Tukey’s test). For L-sized neurons, we observed prolongation of the AP rising time, AP falling time, and AP duration in neurons affected by CSD (p < 0.05, pairwise comparison test). In conclusion, our study provides new insights into the underlying mechanisms of migraine pain and abnormal somatosensation. CSD and serotonin depletion promote the transmission of pain signals through the peripheral sensitization process of nociceptive small-to-medium-sized trigeminal ganglion neurons, as well as nociceptive and non-nociceptive large-sized trigeminal ganglion neurons

Acceptability of Carraguard vaginal gel use among Thai couples

Objectives: To evaluate the acceptability of candidate microbicide Carraguard among couples participating in a safety trial. Study Design: A 6-month randomized, placebo-controlled trial was conducted in sexually active, low-risk couples in Thailand. Methods: Couples who were monogamous, HIV uninfected, and not regular condom users were enrolled. Acceptability data were collected through structured questionnaires at repeated intervals. At the closing study visit, participants were asked questions about hypothetical product characteristics and future use. Compliance with gel use was assessed by questionnaires, coital diaries, and tracking of used and unused applicators. Results: Among 55 enrolled couples, follow up and adherence with gel use were high and sustained, with 80% of women using gel in over 95% of vaginal sex acts. Because acceptability results from Carraguard and placebo arms were similar, they were combined for this analysis. Overall, 92% of women and 83% of men liked the gel somewhat or very much; 66% of women and 72% of men reported increased sexual pleasure with gel use; and 55% of women and 62% of men reported increased frequency of intercourse. Only 15% of women but 43% of men thought that gel could be used without the man knowing. Although men and women had similar views overall, concordance within couples was low, with no kappa coefficients above 0.31. Conclusion: Carraguard gel use was acceptable to low-risk couples in northern Thailand. Reported associations between gel use and increased sexual pleasure and frequency suggest a potential to market microbicide products for both disease prevention and enhancement of pleasure