SummaryMenthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5−/− mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.
Auditory information is initially processed in the cochlear nuclei before being relayed to the brain. The cochlear nuclei are subdivided into dorsal, anterior ventral, and posterior ventral domains, each containing several subtypes of neurons that are thought to play discrete roles in the processing of sound. However, the ontogeny of these neurons is poorly understood, and this gap in knowledge hampers efforts to understand the basic neural circuitry of this nucleus. Here, we reveal that Bhlhb5 is expressed in both excitatory (unipolar brush cells) and inhibitory neurons (cartwheel cells) of the DCN during development. To gain genetic access to Bhlhb5-expressing neurons in the DCN, we generated a Bhlhb5::flpo knockin allele. Using an intersectional genetic strategy, we labeled cartwheel cells, thereby providing proof of concept that subpopulations of Bhlhb5-expressing neurons can be genetically targeted. Moreover, fate-mapping experiments using this allele revealed that Bhlhb5 is required for the proper development of the DCN, since mice lacking Bhlhb5 showed a dramatically diminished number of neurons, including unipolar brush and cartwheel cells. Intriguingly, the Bhlhb5::flpo allele also genetically labels numerous other regions of the nervous system that process sensory input, including the dorsal horn, the retina, and the nucleus of the lateral olfactory tract, hinting at a more general role for Bhlhb5 in the development of neurons that mediate sensory integration.
Size variance among similarly aged individuals within populations is a pattern common to many organisms that is a result of interactions between intrinsic and extrinsic traits of individuals. While genetic and maternal effects, as well as physiological and behavioral traits have been shown to contribute to size variation in animal populations, teasing apart the influence of such factors on individual growth rates remain a challenge. Furthermore, tracing the effects of these interactions across life stages and in shaping adult phenotypes also requires further exploration. In this study we investigated the relationship between genetics, hatching patterns, behaviors, neuroendocrine stress axis activity and variance in growth and metamorphosis among same-aged larval amphibians. Through parallel experiments we found that in the absence of conspecific interactions, hatch time and to a lesser extent egg clutch identity (i.e. genetics and maternal effects) influenced the propensity for growth and development in individual tadpoles and determined metamorphic traits. Within experimental groups we found that variance in growth rates was associated with size-dependent foraging behaviors and responses to food restriction. We also found an inverse relationship between glucocorticoid (GC) hormone levels and body mass and developmental stage among group-reared tadpoles, which suggests that GC expression plays a role in regulating differing within-population growth trajectories in response to density-dependent conditions. Taken together these findings suggest that factors that influence hatching conditions can have long-term effects on growth and development. These results also raise compelling questions regarding the extent to which maternal and genetic factors influence physiological and behavioral profiles in amphibians.
ObjectiveLittle is known about the prevalence of continued opioid use following aneurysmal subarachnoid hemorrhage (aSAH) despite guidelines recommending their use during the acute phase of disease. We sought to determine prevalence of opioid use following aSAH and test the hypothesis that acute pain and higher inpatient opioid dose increased outpatient opioid use.MethodsWe reviewed consecutively admitted aSAH patients from November 2015 through September 2019. We retrospectively collected pain scores and daily doses of analgesics. Pain burden was calculated as area under the pain-time curve. Univariate and multivariable regression models determined risk factors for continued opioid use at discharge and outpatient follow-up.ResultsWe identified 234 aSAH patients with outpatient follow-up. Continued opioid use was common at discharge (55% of patients) and follow-up (47% of patients, median 63 (IQR 49–96) days from admission). Pain burden, craniotomy, and racial-ethnic minority status were associated with discharge opioid prescription in multivariable analysis. At outpatient follow-up, pain burden (OR 1.88, 95% CI 1.5–2.4), depression (OR 3.1, 95% CI 1.1–8.8), and racial-ethnic minority status (OR 2.1, 95% CI 1.1–4.0) were independently associated with continued opioid use while inpatient opioid dose was not.ConclusionContinued opioid use following aSAH is prevalent and related to refractory pain during acute illness, but not inpatient opioid dose. More efficacious analgesic strategies are needed to reduce continued opioid use in patients following aSAH.Classification of evidenceThis study provides Class II evidence that continued opioid use following aSAH is associated with refractory pain during acute illness but not hospital opioid exposure.
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