Biology subjects

Castorena, C. M.

Publications and source records attributed to Castorena, C. M..

4 recordsLinked to original sources

bioRxiv2026

Nociceptor-restricted cannabinoid receptor 1 contributes to chronic but not acute analgesia

Understanding the complex network that regulates pain is fundamental to develop strategies to combat its growing prevalence and increase useful therapeutics. Although extensive literature identifies the importance of cannabinoid receptors and endocannabinoids in controlling pain, their efficacy and loci of action remain debated. To directly test the actions of peripherally restricted cannabinoids and elucidate the minimal circuitry capable of producing cannabinoid-mediated analgesia, we utilized a novel genetic approach that allows for cell-specific reactivation of cannabinoid receptor 1 (CB1R) selectively in peripheral sensory neurons using newly developed CB1R floxed-stop-floxed mice (CB1RLOXTB) crossed with Nav1.8-cre mice (Nav1.8+/-:CB1RLOXTB). Ex vivo and in vivo experiments confirmed successful knockout and reactivation of CB1R. Wildtype littermate controls, but neither Nav1.8+/-:CB1RLOXTB nor CB1RLOXTB animals, exhibited robust analgesia after systemic WIN55,212-2 (WIN) treatment in the tail flick assay. Furthermore, the presence of CB1R on Nav1.8 neurons was not associated with either a difference in the development of inflammatory pain or the response to WIN. However, after neuropathic injury, CB1RLOXTB animals displayed an earlier onset of both mechanical and thermal hypersensitivity than their Nav1.8+/-:CB1RLOXTB or wildtype counterparts, suggesting a dual role for CB1R in inflammatory and neuropathic pain. These studies represent an important approach to further improve our mechanistic understanding of cannabinoid modulation of pain in the nervous system and begins to settle long-standing controversies in cannabinoid literature. Table of ContentsPeripherally restricted cannabinoids show strong preclinical analgesic efficacy but have not translated clinically. Using a genetic model restricting CB1R to Nav1.8-expressing sensory neurons, we show peripheral neuronal endocannabinoid signaling is required for chronic, but not acute pain modulation. This dissociation suggests clinical failures may reflect testing peripheral cannabinoids in acute rather than chronic pain paradigms, informing future translational strategies.

neuroscience↗

bioRxiv2026

Adrβ2 in skeletal muscle cells is required for exercise-induced Pgc1α but not for metabolic benefits of exercise on diet-induced obesity

{beta}2-Adrenergic receptor (Adr{beta}2) is the most abundant form of adrenergic receptors in skeletal muscle. Our previous studies have shown that the ventromedial hypothalamic nucleus (VMH) regulates metabolic benefits of exercise, potentially by skeletal muscle Adr{beta}2. Although a large body of literature has shown the importance of Adr{beta}2 on skeletal muscle physiology, it remains unexplored whether skeletal muscle Adr{beta}2 contributes to metabolic benefits of exercise, such as prevention of diet-induced obesity (DIO). Here, we generated mice lacking Adr{beta}2 in skeletal muscle cells (SKMAdr{beta}2) and tested whether SKMAdr{beta}2 is required for metabolic benefits of exercise on DIO. Deletion of SKMAdr{beta}2 completely abolished the induction of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1) in skeletal muscle by {beta}2-agonist, which is a potent activator of Pgc-1. Exercise upregulates Pgc-1, which regulates a broad range of skeletal muscle physiology, including hypertrophy and mitochondrial function. Deletion of SKMAdr{beta}2 hampers augmented Pgc-1 in skeletal muscle by a single bout of exercise. Intriguingly, we found that deletion of SKMAdr{beta}2 increased endurance capacity. Further, our data showed that body weight in DIO mice lacking SKMAdr{beta}2 is comparable to that of control DIO mice during exercise training, suggesting that deletion of SKMAdr{beta}2 did not affect the metabolic benefits of exercise in DIO. Collectively, our data indicate that SKMAdr{beta}2 contributes to exercise-induced transcriptional changes and endurance capacity, however, it is not required for exercise benefits on bodyweight in DIO mice.

physiology↗

bioRxiv2024

Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia

Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to opioid-based treatments. Here we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in male and female mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by CB1 receptors (CB1Rs) within the VTA as VTA CB1R conditional knockout, counteracts JZL184s effects. Conversely, pharmacologically enhancing the levels of the other eCB, anandamide (AEA), by inhibition of fatty acid amide hydrolase (FAAH) has no effect on opioid reward or analgesia. Using fiber photometry with fluorescent sensors for calcium and dopamine (DA), we find that enhancing 2-AG levels diminishes opioid reward-related nucleus accumbens (NAc) activity and DA neurotransmission. Together these findings reveal that 2-AG counteracts the rewarding properties of opioids and provides a potential adjunctive therapeutic strategy for opioid-related analgesic treatments.

neuroscience↗

bioRxiv2017

Forward Genetic ENU Mutagenesis Screen for Mouse Models of Chronic Fatigue Identifies a Novel Mutation in Slc2a4 (GLUT4)

In a screen of voluntary wheel-running behavior designed to identify genetic mouse models of chronic fatigue in ENU mutagenized C57BL/6J mice, we discovered two lines that showed aberrant wheel-running patterns. These lines both stem from a single original founder identified as a low body-weight candidate in a recessive screen. Progeny from both of these lines showed the abnormal wheel-running behavior, with affected mice showing significantly lower daily activity levels than unaffected mice. They also exhibited low amplitude circadian rhythms, consisting of lower activity levels during the normal active phase, and increased levels of activity during the rest or light phase, but only a modest alteration in free-running period. Their activity is not consolidated into longer bouts, but is frequently interrupted with periods of inactivity throughout the dark phase of the light-dark (LD) cycle. As seen with the low body weight, expression of the behavioral phenotypes in offspring of strategic crosses was consistent with a recessive heritance pattern. Mapping of these phenotypic abnormalities showed linkage to a single locus on chromosome 11, and whole exome sequencing (WES) identified a single point mutation in the Slc2a4 gene encoding the GLUT4 insulin-responsive glucose transporter. The single nucleotide change (A to T) was found in the distal end of exon 10, and results in a premature stop (Y440*). To our knowledge, this is the first time a mutation in this gene has been shown to result in extensive changes in general behavioral patterns.\n\nSIGNIFICANCE STATEMENTChronic fatigue is a debilitating and devastating disorder with widespread consequences for both the patient and the persons around them, but effective treatment strategies are lacking. The identification of novel genetic mouse models of chronic fatigue may prove invaluable for the study of its underlying physiological mechanisms and for the testing of treatments and interventions. A novel mutation in Slc2a4 (GLUT4) was identified in a forward mutagenesis screen because affected mice showed abnormal daily patterns and levels of wheel running consistent with chronic fatigue. This new mouse model may shed light on the pathophysiology of chronic fatigue.

genetics↗